* 107300

SERPIN PEPTIDASE INHIBITOR, CLADE C (ANTITHROMBIN), MEMBER 1; SERPINC1


Alternative titles; symbols

ANTITHROMBIN III; AT3
ANTITHROMBIN
HEPARIN COFACTOR I


HGNC Approved Gene Symbol: SERPINC1

Cytogenetic location: 1q25.1     Genomic coordinates (GRCh38): 1:173,903,800-173,917,327 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q25.1 Thrombophilia 7 due to antithrombin III deficiency 613118 AD, AR 3

TEXT

Description

Antithrombin III is the most important inhibitor of thrombin (176930) and other coagulation proteinases. It belongs to the serine proteinase inhibitor (serpin) superfamily of inhibitors and structurally related proteins, which contain reactive centers that have evolved to attract and entrap certain proteinases. Inherited antithrombin III deficiency (AT3D; 613118) is a risk factor for the early development of venous thromboembolism (THPH7) (summary by Lane et al., 1994).

Antithrombin III regulates clot formation both by inhibiting thrombin activity directly and by interfering with earlier stages of the clotting cascade. Rosenberg and Bauer (1987) gave an excellent review of defects in the anticoagulant systems. They wrote as follows: 'The coagulation cascade can be pictured as a series of reactions in which a zymogen, a cofactor, and a converting enzyme interact to form a multimolecular complex on a natural surface. In each case, the 4 reactants must be present if the conversion of a zymogen to the corresponding serine protease is to take place at any significant rate. The principal natural anticoagulant systems that are able to exert damping effects on the various steps of the cascade are the heparin-antithrombin and protein C-thrombomodulin mechanisms that regulate the serine proteases and the cofactors or activated cofactors, respectively.'


Cloning and Expression

Bock et al. (1982) cloned an AT3 cDNA from a human liver cDNA library. Bjork et al. (1981, 1982) also cloned and characterized the AT3 gene, which encodes a deduced mature secreted peptide of 432 amino acids, 6 of which are cysteines forming 3 disulfide bonds. The protein has 4 glycosylation sites. It is synthesized with a 32-residue leader sequence cleaved prior to its secretion from the hepatocyte into the blood. The protein contains 2 important functional domains, the reactive center and the glycosaminoglycan-binding site. The reactive center is located near the C terminus, with the proteinase target cleavage site on the inhibitor at arg393-ser394. The glycosaminoglycan-binding region is located in the N terminus and is involved in the interaction with heparin and certain endothelial cell surface heparan sulfate proteoglycans. The reactive center and the heparin-binding site are conformationally linked; induced perturbations of one may influence the function of the other (summary by Lane et al., 1994).


Gene Structure

The AT3 gene has 7 exons. It contains 9 complete and 1 partial repetitive ALU sequence elements, which occur in the introns of the gene at a higher frequency (about 22% of the intron sequence) than in the genome as a whole (about 5%) (Chandra et al., 1983; Olds et al., 1993).


Mapping

Using a purified cDNA probe of the AT3 gene and a series of human/Chinese hamster cell hybrids, Kao et al. (1984) assigned the gene to chromosome 1 by Southern blot analysis. Kao et al. (1984) assigned the AT3 gene to 1p31.3-qter.

By in situ hybridization and quantitative analysis of DNA dosage in carriers of chromosome 1 deletions, Bock et al. (1985) assigned AT3 to 1q23-q25. Pakstis et al. (1989) reported linkage data between AT3 and the anonymous DNA fragment D1S75 (maximum lod score = 4.67 at theta = 11.4). In a linkage map of chromosome 1 prepared by Rouleau et al. (1990), it was concluded that AT3 lies about 17 cM distal to FY (110700).


Molecular Genetics

Prochownik et al. (1983) found deletion of the AT3 gene in affected members of a family with AT-III deficiency (613118) but no deletion in affected members of another family. A common DNA polymorphism was found in the gene at codons 304 and 305, which code for leucine and glutamine, respectively, and are either CTGCAA or CTGCAG. Although these are synonymous in amino acid code, they differ with respect to Pst1 restriction, the former not being cleaved.

In 1 of 16 kindreds with AT-III deficiency, Bock and Prochownik (1987) identified hemizygosity of the AT3 locus. In the remaining 15 kindreds, 2 copies of the AT3 gene were present and appeared to be grossly normal at the level of whole genome Southern blotting. This suggested to the authors that small deletions, insertions or limited nucleotide substitutions in the AT3 gene, or 'trans-acting' defects involving the processing, modification, or secretion of biologically active AT3 were responsible for the great majority of the abnormalities.

Using DNA probes, Sacks et al. (1988) found no evidence of gene deletion in 2 families with inherited antithrombin III deficiency. However, linkage analysis showed close linkage (no recombination) between the AT3 gene, as marked by a common polymorphism, and the disorder.

Borg et al. (1988) identified a novel AT-III variant that showed defective heparin binding (107300.0016). This and other mutant forms of AT-III that showed a heparin-binding defect suggested that arginine-47 is a prime heparin-binding site in antithrombin. Borg et al. (1990) studied the basis of reduced heparin affinity.

Leone et al. (1988) used crossed immunoelectrofocusing (CIEF) to investigate molecular heterogeneity in 16 families with congenital defects of AT-III. Of these, 8 families had quantitative deficiency of AT-III and showed a normal CIEF pattern. Of the 8 AT-III molecular variants studied, 6 had 1 of 2 abnormal patterns, depending on whether they were variants with defective binding to heparin or variants with defective binding to serine proteases. Two variants that were deficient in the inactivation of serine proteases showed a normal CIEF pattern.

Wu et al. (1989) used PCR to demonstrate a DNA length polymorphism 5-prime to the AT3 gene due to the presence of 32- or 108-bp nonhomologous DNA segments (Bock and Levitan, 1983). Mutations at residues pro41 and arg47 lead to loss of heparin binding, whereas mutations at residues arg393 and ser394 of the reactive site results in a loss of thrombin inhibitory activity.

Grundy et al. (1991) pointed out that although AT-III deficiency usually follows an autosomal dominant pattern of inheritance, a few patients with defective heparin binding have been shown to be homozygous for a lesion in the arg47 residue (see 107300.0003, 107300.0015).

Classification of Antithrombin Variants

Sas (1988) and De Stefano and Leone (1989) addressed the question of classification of mutant forms of antithrombin III leading to deficiency. Sas (1988) commented on the confused state of the classification of AT-III variants and used the term 'toponym' for the geographic names assigned to variants.

Manson et al. (1989) classified mutations in the AT3 gene as CRM-negative (also referred to as 'classic' or type I) and CRM-positive (also referred to as 'mutant' or type II) cases; in type II, immunologic methods demonstrate in the plasma protein product from the mutant allele. Manson et al. (1989) further classified the AT-III mutants into those involving 1 of the 2 heparin-binding sites in the N terminus (mutations at pro41 or arg47) and those involving the thrombin-binding region toward the C terminus (mutations in ala382, arg393, ser394, or pro407).

Emmerich et al. (1994) noted that Lane et al. (1993) had proposed a new classification of AT3 genetic abnormalities. Type I (quantitative) deficiencies are predominantly due to nonsense mutations, frameshift mutations, and large deletions, preventing the expression of the mutated allele. Type II (qualitative) deficiencies are due to missense mutations resulting in normal circulating levels of AT3 with either an abnormal reactive site (RS) or an abnormal heparin-binding site (HBS). Amino acid substitutions affecting a domain highly conserved in serpins, i.e., C terminal to P1-prime, result in decreased AT3 circulating levels and prevent both coagulation protease inhibition and heparin-binding affinity; this mutations have been described as having a pleiotropic effect (PE).

Reviews

Blajchman et al. (1992) provided a review of molecular defects underlying inherited antithrombin deficiency.

Lane et al. (1996) gave an extensive review of the molecular genetics of antithrombin deficiency.

Lane et al. (1994) described a database of mutations in the AT3 gene. A recent update was said to list 184 entries: 68 reports of type I 'classical' and 116 reports of type II 'variant' deficiencies.

Perry and Carrell (1996) also provided a catalog of AT3 mutations responsible for types I and II deficiency.

Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).


Animal Model

Cleavage of the carboxyl-terminal loop of antithrombin induces a conformational change in the molecule. O'Reilly et al. (1999) demonstrated that the cleaved conformation of antithrombin had potent antiangiogenic and antitumor activity in mouse models. The latent form of intact antithrombin, which is similar in conformation to the cleaved molecule, also inhibited angiogenesis and tumor growth. O'Reilly et al. (1999) concluded that these data provide further evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis. O'Reilly et al. (1999) found that the cleaved antithrombin potently inhibited endothelial cell proliferation induced by bovine fibroblast growth factor or by vascular endothelial growth factor in a dose-dependent fashion with a half-maximal inhibition seen at 50 to 100 ng/ml. O'Reilly et al. (1999) suggested that cleaved antithrombin and other angiogenesis inhibitors offer the potential for improved efficacy and diminished toxicity in the treatment of cancer and other angiogenesis-dependent diseases.

Green et al. (2003) showed that Drosophila 'necrotic' (nec) mutations can mimic alpha-1-antitrypsin deficiency. They identified 2 nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an amino acid substitution equivalent to that found in Siiyama variant antitrypsin (107400.0039) failed to complement nec-null mutations and demonstrated a dominant temperature-dependent inactivation of the wildtype nec allele. Green et al. (2003) concluded that the Drosophila nec system can be used as a powerful system to study serpin polymerization in vivo.


ALLELIC VARIANTS ( 50 Selected Examples):

.0001 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA404THR
  
RCV000019619

This variant, designated AT-III Oslo, was found in the family first described as an example of thrombophilia due to deficiency of AT-III (613118) by Egeberg (1965). Hultin et al. (1988) provided further information. AT-III Oslo is a type I form of deficiency. AT-III protein is decreased in both the immunologic and the functional assay.


.0002 MOVED TO 107300.0007


.0003 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47CYS
  
RCV000019620

AT-III Toyama was described by Sakuragawa et al. (1983). In a patient with recurrent thrombophlebitis and deficiency of AT-III (613118), Koide et al. (1984) identified homozygosity for AT-III Toyama, an arg47-to-cys substitution. Members of the family who were heterozygous for the mutation were asymptomatic.

This mutation has also been described as AT-III Paris (Wolf et al., 1982), AT-III Padua-2 (Girolami et al., 1983), AT-III Tours (Duchange et al., 1986), AT-III Barcelona-2 (Fontcuberta et al., 1988), AT-III Alger (Fischer et al., 1986), AT-III Amiens, and AT-III Paris-2.

Chasse et al. (1984) identified the abnormality in heterozygous state in 9 members of a French family, all without thrombotic complications. Duchange et al. (1986) confirmed that the mutation (AT-III Tours) in this family was a C-to-T transition leading to an arg47-to-cys substitution. The deficiency in AT-III Tours shows retention of normal activity in the absence of heparin and diminished activity in the presence of heparin, with a decrease or complete loss of heparin-binding ability. Most type 3 deficiencies are silent in the heterozygous state and associated with severe thrombotic disorders only in homozygotes (Boyer et al., 1986; Sakuragawa et al., 1983; Duchange et al., 1987).

This variant, described in homozygous form by Fischer et al. (1986), was shown by Brunel et al. (1987) also to have substitution of cysteine for arginine-47. The same mutation was identified by Perry and Carrell (1989).


.0004 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
   RCV000019621

AT-III Roma was studied by Leone et al. (1983) and De Stefano et al. (1987).


.0005 REMOVED FROM DATABASE


.0006 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
   RCV000019622

In a family with AT-III Trento described by Girolami et al. (1984), only 1 of 5 individuals with the variant showed thrombotic phenomena despite the finding that the variant resulted in an overall decrease in antithrombin III activities (613118). Further study by Girolami et al. (1986) showed that a von Willebrand defect segregated independently in this family. Only the symptomatic proposita and a niece showed the isolated AT III abnormality. The authors noted that the proposita's niece was very young and suggested that there was a strong possibility of her developing thrombosis.


.0007 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA384PRO
  
RCV000019623...

AT-III Vicenza was described by Barbui et al. (1983).

The same variant was described by Aiach et al. (1985) as AT-III Charleville. Molho-Sabatier et al. (1989) demonstrated that the AT-III Charleville mutation represents a substitution of proline for alanine at residue 384.

Perry and Carrell (1989) and Caso et al. (1991) also demonstrated this change, which resulted from a GCA-to-CCA transition in exon 6. This is a reactive site mutation. Pewarchuk et al. (1990) used PCR to identify the same abnormality in a family with an extensive history of deep venous thrombosis (613118).

This variant has also been referred to as AT-III Cambridge I and AT-III Sudbury (Pewarchuk et al., 1990).


.0008 MOVED TO 107300.0003


.0009 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
   RCV000019624

In 4 members of a large Tunisian family, Boyer et al. (1986) identified a qualitative defect of antithrombin III, designated AT-III Fontainebleu. The propositus was a 3-year-year old girl who died from massive intracardiac thrombosis despite oral anticoagulant therapy. Heparin cofactor activity was undetectable in plasma and anti-factor Xa activity was absent. Her parents, first cousins, and her sister had levels of heparin cofactor activity close to 50% of normal. Boyer et al. (1986) concluded that the abnormal protein was present in homozygous state in the propositus and in heterozygous state in her parents and sister. Only the propositus had thrombotic episodes (613118).


.0010 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393PRO
  
RCV000019625

AT-III Pescara, described by Leone et al. (1987) in a family with a high incidence of thrombosis (613118), was shown by Lane et al. (1989) to have a CGT-to-CCT change in the AT3 gene, resulting in substitution of proline for arginine-393. The defect concerned binding to serine proteases.


.0011 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER394LEU
  
RCV000019626

Sambrano et al. (1986) identified a qualitative defect in AT-III, designated AT-III Denver, in a 16-year-old girl who presented with an acute lower extremity deep vein thrombosis (613118) occurring spontaneously 2 months after initiation of oral contraceptives. A qualitative defect was documented in 3 of 7 family members in 2 generations. The structural abnormality was a replacement of serine-394 by leucine. AT-III Denver was studied further by Stephens et al. (1987, 1988).

In AT-III Milano-2, Olds et al. (1989) found a TCG-to-TTG change in codon 394 predicting the same ser394-to-leu substitution. This mutation is defective in serpin activity but binds heparin normally.


.0012 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

SERPINC1, PRO41LEU
  
RCV000019627...

This variant, formerly titled THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY, has been reclassified because its contribution to the phenotype has not been confirmed.

AT-III Clichy, a substitution of leucine for proline-41, was described by Chang and Tran (1986), Aiach et al. (1987), and Molho-Sabatier et al. (1989). The variant has also been called AT-III Clichy-2, AT-III Basel, AT-III Franconville.

Aiach et al. (1987) found the mutation in heterozygous state in a 24-year-old woman presenting with a thoracic outlet syndrome.

Perry and Carrell (1989) described the same substitution in this heparin-binding mutation, which was caused by a CGT-to-CAT change in exon 2.

Olds et al. (1990) noted that this mutation occurs within a CG dinucleotide, a recognized hotspot for single base mutations.

In a woman referred for routine prepregnancy testing and in several members of her family, de Roux et al. (1990) found heterozygosity for the pro41-to-leu mutation. None had had thrombotic complications. Testing of the properties of the mutant AT-III suggested that proline-41 is more involved in the molecular changes induced by heparin than in the primary binding of the activator.


.0013 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, VAL-3GLU
  
RCV000019628...

AT-III Dublin was described by Daly et al. (1987) in heterozygous state in 3 Irish individuals with no evidence of hypercoagulation-related problems. In the course of sequencing the AT3 gene in an AT-III Dublin heterozygote, Daly et al. (1990) identified a valine-to-glutamic acid substitution at position -3 in the signal peptide. A second, unrelated individual being investigated for recurrent thromboses was found to be heterozygous for same mutation. N-terminal sequencing of the antithrombin protein from both heterozygotes showed a truncated antithrombin in which the N-terminal dipeptide is absent. Daly et al. (1990) proposed that the prepeptide mutation redirects signal peptidase cleavage to a site 2 amino acids downstream into the mature protein.

Durr et al. (1992) found this mutation in southwest Germans and Portuguese, with frequencies of 0.007 and 0.00024, respectively.


.0014 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
   RCV000019629

Grau et al. (1988) described a quantitative and qualitative defect of AT-III in 4 members of a Spanish family with a thrombotic tendency (613118). The authors referred to the variant as AT-III Barcelona.


.0015 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47HIS
  
RCV000019630...

Owen et al. (1987) described this heparin-binding defect (AT-III Rouen I), a substitution of histidine at arginine-47 (R47H). Perry and Carrell (1989) found the same substitution, caused by a CCG-to-CTG change in exon 2.

Caso et al. (1990) identified the same mutation, which they called antithrombin Padua I, in several members of a family. No pathologic consequence (i.e., thrombosis) appeared to be associated with the mutation in this family. Caso et al. (1990) stated that the substitution resulted from a change of CGT to CAT in exon 2.

Emmerich et al. (1994) reported 2 brothers with AT-III deficiency (613118) and thromboembolic events who were compound heterozygous for 2 mutations in the AT3 gene: R47H, inherited from the mother, and a 9-bp deletion (107300.0050), probably inherited from the father, who had died from a pulmonary embolism at age 68. The 9-bp deletion results in a substitution of val426 by ala, a deletion of the tripeptide ala427-asn428-pro429, and a shift of the cys430 to position 427, which probably impairs the formation of the last disulfide bond.


.0016 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47SER
  
RCV000019631

Borg et al. (1988) identified heterozygosity for an arg47-to-ser (R47S) substitution in the AT3 gene in a 40-year-old man who was admitted to hospital with a sudden myocardial infarction that lacked extensive coronary artery disease. His 13-year-old daughter displayed the same antithrombin abnormality. The variant, designated AT-III Rouen II, showed defective heparin and heparan sulfate activities. There was no definite family history of thrombosis.


.0017 MOVED TO 107300.0003


.0018 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393CYS
  
RCV000019632

In a 47-year-old patient presenting with recurrent venous thromboembolism (613118), Aiach et al. (1988) identified a reactive site variant, AT-III Avranches, in the AT3 gene that changed arginine-393 to cysteine. They identified the same abnormality with defective serine-protease inhibition in 2 of the patient's relatives.


.0019 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, PRO407LEU
  
RCV000019633

In affected members of a family from Utah with antithrombin III deficiency and thrombosis (613118) (Bock et al., 1985), Bock et al. (1988) identified heterozygosity for a substitution of leucine for proline-407 in the AT3 gene. AT-III Utah results in type I deficiency; antithrombin III shows a 50% decrease in both the immunologic and the functional assay.


.0020 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393CYS
   RCV000019632

AT-III Northwick Park, described by Lane et al. (1987), was shown by Erdjument et al. (1988) to have substitution of cysteine for arginine-393. The same substitution was found by Erdjument et al. (1988) in AT-III Milano-1. The mutation leads to thrombosis (613118).


.0021 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393HIS
  
RCV000019635

AT-III Glasgow, described by Lane et al. (1987), was shown by Erdjument et al. (1988) and by Owen et al. (1988) to have substitution of histidine for arginine-393 and to lead to thrombosis (613118).

Lane et al. (1989) showed that AT-III Sheffield has the same substitution. Owen et al. (1988) also demonstrated replacement of arginine by histidine at residue 393 in a 41-year-old male with a history of thrombotic events. Arginine-393 is located in the site involved in interaction with thrombin; the susceptibility to thrombosis with this mutation is thus explained. Molho-Sabatier et al. (1989) also found the arg393-to-his mutation in a variant form of AT-III.

AT-III Chicago, a functionally inactive antithrombin III associated with thrombotic disease, was found by Erdjument et al. (1989) to have the same substitution.


.0022 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA382THR
  
RCV000019636

In a French-Canadian family, Devraj-Kizuk et al. (1988) demonstrated a structural mutant of AT-III with defective serine protease activity, which they termed AT-III Hamilton. The propositus, a 54-year-old man with a history of recurrent thromboembolic events (613118), and his 2 asymptomatic adult children were heterozygous. Exon 6 showed a G-to-A point mutation in the first base of codon 382, leading to the substitution of threonine for alanine. Alanine-382, 12 residues from the reactive center of the enzyme, is a highly conserved amino acid in the family of serine protease inhibitors known as the serpins. In this reactive site mutation, Perry and Carrell (1989) found substitution of threonine for alanine-382 as a consequence of a GCA-to-ACA change in exon 6.


.0023 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ILE7ASN
  
RCV000019637

Brennan et al. (1988) demonstrated a substitution of asparagine for isoleucine at position 7 in a mutant antithrombin III, designated AT-III Rouen III, isolated from the plasma of a patient with pulmonary embolism (613118). The mutation introduced a new asn-cys-thr glycosylation sequence. The new oligosaccharide attachment site occupied the base of the presumed heparin-binding site, and the finding explained the consequent decrease in heparin affinity. Perry and Carrell (1989) also found this substitution, which was due to an ATC-to-AAC change, as the basis of a molecule defective in heparin binding.


.0024 MOVED TO 107300.0012


.0025 MOVED TO 107300.0003


.0026 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG24CYS
  
RCV000019638...

In a 25-year-old man who unexpectedly developed coronary thrombosis (613118), Borg et al. (1990) identified heterozygosity for a CGC-to-TGC transition at nucleotide 166 in exon 2 of the AT3 gene, resulting in an arg24-to-cys substitution. He inherited the mutation from his asymptomatic father. He inherited a hypofibrinogenemia from his mother. The AT3 mutation, designated AT-III Rouen IV, results in impaired heparin binding.


.0027 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA384SER
  
RCV000019639...

Harper et al. (1991) identified AT-III Cambridge II, which has a substitution of serine for alanine-384. This mutation occurs at the same codon as AT-III Cambridge I (107300.0007). Perry et al. (1991) identified 4 unrelated persons with an identical antithrombin variant, associated in one of them with episodes of recurrent venous thromboses (613118). In each case, the plasma antithrombin concentration was normal and the only functional abnormality was a minor but consistent decrease in the heparin-induced thrombin inhibition, suggesting a mutation at or near the reactive center of the molecule. Amplification and direct sequencing of exon 6 showed a G-to-T mutation at nucleotide 1246, which corresponded to a substitution of serine for alanine at residue 384.


.0028 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP DEL, A
  
RCV000851895

Grundy et al. (1991) identified 2 patients, each from unrelated families segregating AT-III deficiency and a history of thrombosis (613118), who were heterozygous for different frameshift mutations involving the same GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a heterozygous deletion of the A nucleotide, whereas the second had a heterozygous deletion of an A and a G (107300.0029). Grundy et al. (1991) pointed out that the deletion-prone glu245 codon is located within a GAGAG motif that is effectively a short overlapping direct repeat. In addition, a short inverted repeat flanked the site of deletion. They pointed to similar deletion hotspots in the F8, HPRT, HBA2, and HBB genes and pointed out common characteristics of these hotspots.


.0029 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 2-BP DEL, AG
  
RCV001235412

Grundy et al. (1991) identified 2 patients, each from unrelated families segregating AT-III deficiency and a history of thrombosis (613118), who were heterozygous for different frameshift mutations involving the same GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a heterozygous deletion of the A nucleotide (107300.0028), whereas the second had a heterozygous deletion of an A and a G. Grundy et al. (1991) pointed out that the deletion-prone glu245 codon is located within a GAGAG motif that is effectively a short overlapping direct repeat. In addition, a short inverted repeat flanked the site of deletion. They pointed to similar deletion hotspots in the F8, HPRT, HBA2, and HBB genes and pointed out common characteristics of these hotspots.


.0030 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, 780A
  
RCV000019642

In a woman who developed pulmonary embolism during the postpartum period of her first delivery and has AT-III deficiency (613118), Vidaud et al. (1991) identified heterozygosity for an insertion of an adenine at position 780 of the AT3 gene, according to the cDNA numbering of Chandra et al. (1983). The mutation generated a frameshift that modified the amino acid sequence and introduced a premature stop codon at position 232 of the protein. The woman's mother, who also had AT-III deficiency and reported a history of recurrent venous thrombosis, was heterozygous for the mutation.


.0031 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER291PRO
  
RCV000019643

In a woman with type I AT-III deficiency who experienced several deep vein thromboses (613118), Vidaud et al. (1991) identified heterozygosity for a 2-bp deletion at positions 965 and 966 or at 967 and 968. (Because 2 AG dinucleotides were located next to each other, it was impossible to tell which of the 2 was deleted.) The deletion created a new reading frame from lysine-290 on, converting ser291 to proline and introducing a stop codon at position 309 in the protein sequence. Her 2 children were also heterozygous for the mutation and had decreased AT-III levels.


.0032 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASP309LYS
  
RCV000019644

In a 48-year-old man with type I antithrombin III deficiency and a history of thrombotic events (613118), Vidaud et al. (1991) found heterozygosity for a 4-bp deletion in the AT3 gene, resulting in a new reading frame beyond leu308, changing aspartic acid-309 to lysine and resulting in a TGA stop codon at amino acid position 313. One of his sons, who was then 35 years old, was heterozygous for the mutation and had AT-III deficiency but was free of thrombotic events.


.0033 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG129TER
  
RCV000019645...

In 3 patients from 2 apparently unrelated families with thrombophilia due to type Ia AT-III deficiency (613118), Gandrille et al. (1991) identified a heterozygous C-to-T mutation at codon 129 of the AT3 gene, resulting in change from arginine to stop. Olds et al. (1991) reported 4 further kindreds in which the same mutation was associated with type Ia AT-III deficiency and thrombotic disease. They stated that this mutation was present in about 10% of their families with type Ia. (Type Ia is characterized by the presence of only half the normal AT-III concentration in plasma, with no detectable variant protein.) The mutation in AT-III Geneva (107300.0034) occurs at the same codon.


.0034 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG129GLN
  
RCV000019646

In a patient with type Ia deficiency of antithrombin III who had 1 episode of pulmonary embolism (613118), Gandrille et al. (1990) identified heterozygosity for a G-A transition in the AT3 gene, resulting in substitution of glutamine for arginine-129. The finding of mutations at arginine-129 indicates its importance to the heparin-binding site of AT3. The mutation was designated AT-III Geneva.


.0035 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, PRO429LEU
  
RCV000019647

AT-III Budapest was the first type 2a AT-III variant described (Sas et al. (1974, 1975, 1978)). The propositus and several members of the kindred had had thromboembolic episodes (613118). The parents of the propositus were consanguineous.

Olds et al. (1992) showed that the AT-III Budapest allele, for which the propositus was homozygous, contained a single nucleotide substitution leading to the replacement of proline by leucine at codon 429. Proline at this position is highly conserved across the whole of the serpin family of proteins.


.0036 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER349PRO
  
RCV000019648

In affected members of an English family segregating recurrent venous thrombosis (613118), Grundy et al. (1992) identified heterozygosity for a point mutation in exon 4 of the AT3 gene, resulting in substitution of proline for serine-349.


.0037 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, GLY392ASP
  
RCV000019649

Antithrombin III Stockholm, found in a woman who developed a pulmonary embolus (613118) while on oral contraceptives at age 19, was shown by Blajchman et al. (1992) to have a substitution of aspartic acid for glycine-392, resulting from a G-to-A change in the second base of codon 392.


.0038 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, LEU99PHE
  
RCV000019650...

Olds et al. (1992) described a CTC-to-TTC transition at codon 99 of the AT3 gene, altering the normal leucine to phenylalanine. The proband had a history of venous thrombotic disease (613118) and was found to be homozygous for the mutation. The variant protein showed reduced heparin affinity and reduced antiproteinase activity in the presence of either unfractionated heparin or the AT-binding heparin pentasaccharide, when compared to normal AT. The substitution is located near the proposed heparin-binding site.


.0039 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, T, CODON 48
  
RCV000019651

In a patient with antithrombin III deficiency and a proven family history of thromboembolic disease (613118), Daly et al. (1992) identified heterozygosity for a 1-bp insertion (T) in exon 2 of the AT3 gene, causing a frameshift at codon 48 from a valine (GTC) to a cysteine (TGT) and a premature stop codon at position 72. A truncated AT3 protein could not be detected in plasma, suggesting that it failed to be secreted or was rapidly degraded. The mutation was designated AT48(+T).


.0040 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, A, CODON 208
  
RCV000019652

Daly et al. (1992) studied a 37-year-old woman with antithrombin III deficiency and a proven family history of thromboembolic disease (613118). Using PCR and direct sequencing of amplified DNA, they identified an insertion of an A in exon 3B of the AT3 gene, changing codon 208 from AAT (asparagine) to AAA (lysine) and creating a frameshift with a stop codon at position 209. No abnormal AT3 was detected in the plasma. The mutation was designated AT208(+A).


.0041 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP DEL, A, CODON 370
  
RCV000019653

Daly et al. (1992) studied a 24-year-old woman with antithrombin III deficiency and a history of thromboembolic disease (613118). Using PCR and direct sequencing of amplified DNA, they identified a deletion of an A in codon 370 in exon 5 of the AT3 gene, changing AAG (lysine) to AGG (arginine) and resulting in a frameshift with a stop codon at position 375. No abnormal antithrombin protein was detected in the plasma. The mutation was designated AT370(-A).


.0042 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA387VAL
  
RCV000019654

In a patient with recurrent venous thrombosis and an AT-III activity/antigen level consistent with type I AT-III deficiency (613118), White et al. (1992) identified heterozygosity for a C-T transition in the AT3 gene, resulting in an ala387-to-val substitution near the reactive site.


.0043 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER116PRO
  
RCV000019655

In a 33-year-old man who had recurrent cerebral infarctions (613118), Okajima et al. (1993) found a T-to-C transition in exon 3a which resulted in the substitution of proline for serine at codon 116. The patient was heterozygous for the mutation, which lacked affinity for heparin. The variant was designated AT-III Nagasaki.


.0044 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, LEU-10PRO
  
RCV000019656

Most secretory proteins, including antithrombin, are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). Fitches et al. (1998) identified a novel mutation, which affected the central hydrophobic domain of the AT3 signal peptide, in a proband presenting with venous thrombotic disease and type I AT3 deficiency (613118). The mutation was a 2436T-C transition, resulting in a leucine to proline change at the -10 residue of the signal peptide. Fitches et al. (1998) investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT3 cDNAs with mutations affecting the -10 residue. Glycosylated AT3 was secreted from COS-7 cells transfected with wildtype AT3, -10leu deletion, -10val or -10met variants, but not variants with pro, thr, arg, or gly at -10. Cell-free expression of wildtype and variant AT3 cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for the ER. Variant AT3 proteins with pro, thr, arg, or gly at residue -10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested that they had not been translocated into microsomes. The results suggested that the ability of AT3 signal peptide to direct the protein to the ER for cotranslational processing events is critically dependent on maintaining the hydrophobic nature of the region including residue -10. The investigations defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT3 deficiency.


.0045 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASN135THR
  
RCV000019657

In a 25-year-old Italian woman who had experienced no thrombosis and had no family history of venous thrombosis, Bayston et al. (1999) found antithrombin deficiency (613118) with borderline levels (approximately 70% antigen and activity) of antithrombin. Direct sequencing of amplified DNA showed a mutation in codon 135, AAC to ACC, predicting a heterozygous asn135-to-thr substitution. This substitution altered the predicted consensus sequence for glycosylation, asn-X-ser, adjacent to the heparin interaction site of antithrombin. Antithrombin isolated from plasma of the patient by heparin-Sepharose chromatography contained amounts of beta-antithrombin (the very high affinity fraction) greatly increased (approximately 20 to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wildtype and variant protein were translated and then exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represented a novel cause of antithrombin deficiency, removal of glycosylation consensus sequence, and highlighted the potentially important role of beta-antithrombin in regulating coagulation.


.0046 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASN187ASP
  
RCV000019658

Bruce et al. (1994) described thromboembolic disease due to thermolabile conformational changes of AT-III Rouen VI (613118), which carries an asn187-to-asp missense mutation in the AT3 gene.


.0047 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER191PRO
  
RCV000019659

Baud et al. (2001) reported a neonate who died from a fatal cerebral hemorrhage involving the left thalamus following deep cerebral vein thrombosis (613118). The child was heterozygous for a 6472T-C transition in the AT3 gene, resulting in a serine-to-proline substitution at codon 191 (S191P). Antithrombin levels were in the low normal range. An asymptomatic sister, mother, and maternal grandfather had the same mutation. A maternal aunt had suffered an undiagnosed pulmonary embolism presumably secondary to antithrombin III deficiency.


.0048 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, CYS95ARG
  
RCV000019660

Ozawa et al. (1997) described antithrombin III deficiency (613118) caused by a T-to-C transition in the AT3 gene, resulting in a cys95-to-arg (C95R) substitution. Because this cysteine is responsible for the forming of an intramolecular disulfide bond, the mutation ostensibly affects the folding of AT3 molecules. Tanaka et al. (2002) transfected Chinese hamster ovary cells with the cDNA of AT-III Morioka and compared its intracellular fate to that of wildtype AT-III. They found that the mutant AT-III is not transported to the Golgi apparatus and accumulates without degradation in novel structures surrounded by a single membrane derived from the endoplasmic reticulum.


.0049 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 3-BP DEL
  
RCV000019661

In a proband with early-onset thrombosis and antithrombin III deficiency (613118), Raja et al. (2003) identified a heterozygous 3-bp deletion corresponding to the codon for the P1 arginine-393 residue (ARG393DEL). The mutation abolished inhibitor activity toward thrombin and factor Xa, but bound to either full-length or pentasaccharide heparins with substantially higher affinity than that of the normal inhibitor. The authors suggested that the unusually severe thrombosis associated with this mutation may be explained by the ability of antithrombin London to bind endogenous heparan sulfate or heparan molecules and to thereby block activation of the normal inhibitor.


.0050 THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 9-BP DEL, NT13395
  
RCV000019662

For discussion of the 9-bp deletion in the SERPINC1 gene that was found in compound heterozygous state in 2 brothers with antithrombin III deficiency (613118) by Emmerich et al., 1994, see 107300.0015.


See Also:

REFERENCES

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Carol A. Bocchini - updated : 11/17/2009
Ada Hamosh - updated : 4/15/2003
Ada Hamosh - updated : 1/25/2002
Victor A. McKusick - updated : 2/28/2001
Victor A. McKusick - updated : 1/19/2000
Ada Hamosh - updated : 9/15/1999
Victor A. McKusick - updated : 2/1/1999
Creation Date:
Victor A. McKusick : 6/16/1986
carol : 03/29/2022
carol : 09/06/2017
carol : 07/18/2016
carol : 7/14/2016
joanna : 7/13/2016
mcolton : 8/19/2015
carol : 7/23/2015
carol : 2/10/2015
mcolton : 2/6/2015
terry : 11/29/2012
terry : 7/27/2012
joanna : 4/30/2012
carol : 3/1/2012
carol : 6/22/2011
carol : 4/8/2011
carol : 6/30/2010
terry : 1/21/2010
terry : 12/1/2009
carol : 11/19/2009
carol : 11/18/2009
carol : 11/17/2009
terry : 11/16/2009
terry : 11/16/2009
carol : 11/13/2009
terry : 6/3/2009
joanna : 3/17/2004
alopez : 4/17/2003
terry : 4/15/2003
alopez : 5/2/2002
terry : 3/13/2002
alopez : 1/30/2002
terry : 1/25/2002
terry : 3/26/2001
alopez : 3/1/2001
terry : 2/28/2001
terry : 12/5/2000
mcapotos : 1/24/2000
terry : 1/19/2000
carol : 9/17/1999
terry : 9/15/1999
terry : 4/30/1999
carol : 2/15/1999
terry : 2/1/1999
dkim : 7/21/1998
dkim : 6/30/1998
alopez : 5/14/1998
mark : 7/16/1997
alopez : 7/16/1997
alopez : 7/16/1997
mark : 12/26/1996
terry : 11/12/1996
mark : 1/30/1996
mark : 1/24/1996
terry : 12/22/1994
jason : 7/1/1994
mimadm : 3/28/1994
carol : 2/23/1994
carol : 7/9/1993
carol : 6/3/1993

* 107300

SERPIN PEPTIDASE INHIBITOR, CLADE C (ANTITHROMBIN), MEMBER 1; SERPINC1


Alternative titles; symbols

ANTITHROMBIN III; AT3
ANTITHROMBIN
HEPARIN COFACTOR I


HGNC Approved Gene Symbol: SERPINC1

SNOMEDCT: 36351005;   ICD10CM: D68.59;  


Cytogenetic location: 1q25.1     Genomic coordinates (GRCh38): 1:173,903,800-173,917,327 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q25.1 Thrombophilia 7 due to antithrombin III deficiency 613118 Autosomal dominant; Autosomal recessive 3

TEXT

Description

Antithrombin III is the most important inhibitor of thrombin (176930) and other coagulation proteinases. It belongs to the serine proteinase inhibitor (serpin) superfamily of inhibitors and structurally related proteins, which contain reactive centers that have evolved to attract and entrap certain proteinases. Inherited antithrombin III deficiency (AT3D; 613118) is a risk factor for the early development of venous thromboembolism (THPH7) (summary by Lane et al., 1994).

Antithrombin III regulates clot formation both by inhibiting thrombin activity directly and by interfering with earlier stages of the clotting cascade. Rosenberg and Bauer (1987) gave an excellent review of defects in the anticoagulant systems. They wrote as follows: 'The coagulation cascade can be pictured as a series of reactions in which a zymogen, a cofactor, and a converting enzyme interact to form a multimolecular complex on a natural surface. In each case, the 4 reactants must be present if the conversion of a zymogen to the corresponding serine protease is to take place at any significant rate. The principal natural anticoagulant systems that are able to exert damping effects on the various steps of the cascade are the heparin-antithrombin and protein C-thrombomodulin mechanisms that regulate the serine proteases and the cofactors or activated cofactors, respectively.'


Cloning and Expression

Bock et al. (1982) cloned an AT3 cDNA from a human liver cDNA library. Bjork et al. (1981, 1982) also cloned and characterized the AT3 gene, which encodes a deduced mature secreted peptide of 432 amino acids, 6 of which are cysteines forming 3 disulfide bonds. The protein has 4 glycosylation sites. It is synthesized with a 32-residue leader sequence cleaved prior to its secretion from the hepatocyte into the blood. The protein contains 2 important functional domains, the reactive center and the glycosaminoglycan-binding site. The reactive center is located near the C terminus, with the proteinase target cleavage site on the inhibitor at arg393-ser394. The glycosaminoglycan-binding region is located in the N terminus and is involved in the interaction with heparin and certain endothelial cell surface heparan sulfate proteoglycans. The reactive center and the heparin-binding site are conformationally linked; induced perturbations of one may influence the function of the other (summary by Lane et al., 1994).


Gene Structure

The AT3 gene has 7 exons. It contains 9 complete and 1 partial repetitive ALU sequence elements, which occur in the introns of the gene at a higher frequency (about 22% of the intron sequence) than in the genome as a whole (about 5%) (Chandra et al., 1983; Olds et al., 1993).


Mapping

Using a purified cDNA probe of the AT3 gene and a series of human/Chinese hamster cell hybrids, Kao et al. (1984) assigned the gene to chromosome 1 by Southern blot analysis. Kao et al. (1984) assigned the AT3 gene to 1p31.3-qter.

By in situ hybridization and quantitative analysis of DNA dosage in carriers of chromosome 1 deletions, Bock et al. (1985) assigned AT3 to 1q23-q25. Pakstis et al. (1989) reported linkage data between AT3 and the anonymous DNA fragment D1S75 (maximum lod score = 4.67 at theta = 11.4). In a linkage map of chromosome 1 prepared by Rouleau et al. (1990), it was concluded that AT3 lies about 17 cM distal to FY (110700).


Molecular Genetics

Prochownik et al. (1983) found deletion of the AT3 gene in affected members of a family with AT-III deficiency (613118) but no deletion in affected members of another family. A common DNA polymorphism was found in the gene at codons 304 and 305, which code for leucine and glutamine, respectively, and are either CTGCAA or CTGCAG. Although these are synonymous in amino acid code, they differ with respect to Pst1 restriction, the former not being cleaved.

In 1 of 16 kindreds with AT-III deficiency, Bock and Prochownik (1987) identified hemizygosity of the AT3 locus. In the remaining 15 kindreds, 2 copies of the AT3 gene were present and appeared to be grossly normal at the level of whole genome Southern blotting. This suggested to the authors that small deletions, insertions or limited nucleotide substitutions in the AT3 gene, or 'trans-acting' defects involving the processing, modification, or secretion of biologically active AT3 were responsible for the great majority of the abnormalities.

Using DNA probes, Sacks et al. (1988) found no evidence of gene deletion in 2 families with inherited antithrombin III deficiency. However, linkage analysis showed close linkage (no recombination) between the AT3 gene, as marked by a common polymorphism, and the disorder.

Borg et al. (1988) identified a novel AT-III variant that showed defective heparin binding (107300.0016). This and other mutant forms of AT-III that showed a heparin-binding defect suggested that arginine-47 is a prime heparin-binding site in antithrombin. Borg et al. (1990) studied the basis of reduced heparin affinity.

Leone et al. (1988) used crossed immunoelectrofocusing (CIEF) to investigate molecular heterogeneity in 16 families with congenital defects of AT-III. Of these, 8 families had quantitative deficiency of AT-III and showed a normal CIEF pattern. Of the 8 AT-III molecular variants studied, 6 had 1 of 2 abnormal patterns, depending on whether they were variants with defective binding to heparin or variants with defective binding to serine proteases. Two variants that were deficient in the inactivation of serine proteases showed a normal CIEF pattern.

Wu et al. (1989) used PCR to demonstrate a DNA length polymorphism 5-prime to the AT3 gene due to the presence of 32- or 108-bp nonhomologous DNA segments (Bock and Levitan, 1983). Mutations at residues pro41 and arg47 lead to loss of heparin binding, whereas mutations at residues arg393 and ser394 of the reactive site results in a loss of thrombin inhibitory activity.

Grundy et al. (1991) pointed out that although AT-III deficiency usually follows an autosomal dominant pattern of inheritance, a few patients with defective heparin binding have been shown to be homozygous for a lesion in the arg47 residue (see 107300.0003, 107300.0015).

Classification of Antithrombin Variants

Sas (1988) and De Stefano and Leone (1989) addressed the question of classification of mutant forms of antithrombin III leading to deficiency. Sas (1988) commented on the confused state of the classification of AT-III variants and used the term 'toponym' for the geographic names assigned to variants.

Manson et al. (1989) classified mutations in the AT3 gene as CRM-negative (also referred to as 'classic' or type I) and CRM-positive (also referred to as 'mutant' or type II) cases; in type II, immunologic methods demonstrate in the plasma protein product from the mutant allele. Manson et al. (1989) further classified the AT-III mutants into those involving 1 of the 2 heparin-binding sites in the N terminus (mutations at pro41 or arg47) and those involving the thrombin-binding region toward the C terminus (mutations in ala382, arg393, ser394, or pro407).

Emmerich et al. (1994) noted that Lane et al. (1993) had proposed a new classification of AT3 genetic abnormalities. Type I (quantitative) deficiencies are predominantly due to nonsense mutations, frameshift mutations, and large deletions, preventing the expression of the mutated allele. Type II (qualitative) deficiencies are due to missense mutations resulting in normal circulating levels of AT3 with either an abnormal reactive site (RS) or an abnormal heparin-binding site (HBS). Amino acid substitutions affecting a domain highly conserved in serpins, i.e., C terminal to P1-prime, result in decreased AT3 circulating levels and prevent both coagulation protease inhibition and heparin-binding affinity; this mutations have been described as having a pleiotropic effect (PE).

Reviews

Blajchman et al. (1992) provided a review of molecular defects underlying inherited antithrombin deficiency.

Lane et al. (1996) gave an extensive review of the molecular genetics of antithrombin deficiency.

Lane et al. (1994) described a database of mutations in the AT3 gene. A recent update was said to list 184 entries: 68 reports of type I 'classical' and 116 reports of type II 'variant' deficiencies.

Perry and Carrell (1996) also provided a catalog of AT3 mutations responsible for types I and II deficiency.

Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).


Animal Model

Cleavage of the carboxyl-terminal loop of antithrombin induces a conformational change in the molecule. O'Reilly et al. (1999) demonstrated that the cleaved conformation of antithrombin had potent antiangiogenic and antitumor activity in mouse models. The latent form of intact antithrombin, which is similar in conformation to the cleaved molecule, also inhibited angiogenesis and tumor growth. O'Reilly et al. (1999) concluded that these data provide further evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis. O'Reilly et al. (1999) found that the cleaved antithrombin potently inhibited endothelial cell proliferation induced by bovine fibroblast growth factor or by vascular endothelial growth factor in a dose-dependent fashion with a half-maximal inhibition seen at 50 to 100 ng/ml. O'Reilly et al. (1999) suggested that cleaved antithrombin and other angiogenesis inhibitors offer the potential for improved efficacy and diminished toxicity in the treatment of cancer and other angiogenesis-dependent diseases.

Green et al. (2003) showed that Drosophila 'necrotic' (nec) mutations can mimic alpha-1-antitrypsin deficiency. They identified 2 nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an amino acid substitution equivalent to that found in Siiyama variant antitrypsin (107400.0039) failed to complement nec-null mutations and demonstrated a dominant temperature-dependent inactivation of the wildtype nec allele. Green et al. (2003) concluded that the Drosophila nec system can be used as a powerful system to study serpin polymerization in vivo.


ALLELIC VARIANTS 50 Selected Examples):

.0001   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA404THR
SNP: rs121909546, ClinVar: RCV000019619

This variant, designated AT-III Oslo, was found in the family first described as an example of thrombophilia due to deficiency of AT-III (613118) by Egeberg (1965). Hultin et al. (1988) provided further information. AT-III Oslo is a type I form of deficiency. AT-III protein is decreased in both the immunologic and the functional assay.


.0002   MOVED TO 107300.0007


.0003   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47CYS
SNP: rs121909547, gnomAD: rs121909547, ClinVar: RCV000019620

AT-III Toyama was described by Sakuragawa et al. (1983). In a patient with recurrent thrombophlebitis and deficiency of AT-III (613118), Koide et al. (1984) identified homozygosity for AT-III Toyama, an arg47-to-cys substitution. Members of the family who were heterozygous for the mutation were asymptomatic.

This mutation has also been described as AT-III Paris (Wolf et al., 1982), AT-III Padua-2 (Girolami et al., 1983), AT-III Tours (Duchange et al., 1986), AT-III Barcelona-2 (Fontcuberta et al., 1988), AT-III Alger (Fischer et al., 1986), AT-III Amiens, and AT-III Paris-2.

Chasse et al. (1984) identified the abnormality in heterozygous state in 9 members of a French family, all without thrombotic complications. Duchange et al. (1986) confirmed that the mutation (AT-III Tours) in this family was a C-to-T transition leading to an arg47-to-cys substitution. The deficiency in AT-III Tours shows retention of normal activity in the absence of heparin and diminished activity in the presence of heparin, with a decrease or complete loss of heparin-binding ability. Most type 3 deficiencies are silent in the heterozygous state and associated with severe thrombotic disorders only in homozygotes (Boyer et al., 1986; Sakuragawa et al., 1983; Duchange et al., 1987).

This variant, described in homozygous form by Fischer et al. (1986), was shown by Brunel et al. (1987) also to have substitution of cysteine for arginine-47. The same mutation was identified by Perry and Carrell (1989).


.0004   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
ClinVar: RCV000019621

AT-III Roma was studied by Leone et al. (1983) and De Stefano et al. (1987).


.0005   REMOVED FROM DATABASE


.0006   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
ClinVar: RCV000019622

In a family with AT-III Trento described by Girolami et al. (1984), only 1 of 5 individuals with the variant showed thrombotic phenomena despite the finding that the variant resulted in an overall decrease in antithrombin III activities (613118). Further study by Girolami et al. (1986) showed that a von Willebrand defect segregated independently in this family. Only the symptomatic proposita and a niece showed the isolated AT III abnormality. The authors noted that the proposita's niece was very young and suggested that there was a strong possibility of her developing thrombosis.


.0007   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA384PRO
SNP: rs121909548, gnomAD: rs121909548, ClinVar: RCV000019623, RCV003886364

AT-III Vicenza was described by Barbui et al. (1983).

The same variant was described by Aiach et al. (1985) as AT-III Charleville. Molho-Sabatier et al. (1989) demonstrated that the AT-III Charleville mutation represents a substitution of proline for alanine at residue 384.

Perry and Carrell (1989) and Caso et al. (1991) also demonstrated this change, which resulted from a GCA-to-CCA transition in exon 6. This is a reactive site mutation. Pewarchuk et al. (1990) used PCR to identify the same abnormality in a family with an extensive history of deep venous thrombosis (613118).

This variant has also been referred to as AT-III Cambridge I and AT-III Sudbury (Pewarchuk et al., 1990).


.0008   MOVED TO 107300.0003


.0009   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
ClinVar: RCV000019624

In 4 members of a large Tunisian family, Boyer et al. (1986) identified a qualitative defect of antithrombin III, designated AT-III Fontainebleu. The propositus was a 3-year-year old girl who died from massive intracardiac thrombosis despite oral anticoagulant therapy. Heparin cofactor activity was undetectable in plasma and anti-factor Xa activity was absent. Her parents, first cousins, and her sister had levels of heparin cofactor activity close to 50% of normal. Boyer et al. (1986) concluded that the abnormal protein was present in homozygous state in the propositus and in heterozygous state in her parents and sister. Only the propositus had thrombotic episodes (613118).


.0010   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393PRO
SNP: rs121909549, gnomAD: rs121909549, ClinVar: RCV000019625

AT-III Pescara, described by Leone et al. (1987) in a family with a high incidence of thrombosis (613118), was shown by Lane et al. (1989) to have a CGT-to-CCT change in the AT3 gene, resulting in substitution of proline for arginine-393. The defect concerned binding to serine proteases.


.0011   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER394LEU
SNP: rs121909550, ClinVar: RCV000019626

Sambrano et al. (1986) identified a qualitative defect in AT-III, designated AT-III Denver, in a 16-year-old girl who presented with an acute lower extremity deep vein thrombosis (613118) occurring spontaneously 2 months after initiation of oral contraceptives. A qualitative defect was documented in 3 of 7 family members in 2 generations. The structural abnormality was a replacement of serine-394 by leucine. AT-III Denver was studied further by Stephens et al. (1987, 1988).

In AT-III Milano-2, Olds et al. (1989) found a TCG-to-TTG change in codon 394 predicting the same ser394-to-leu substitution. This mutation is defective in serpin activity but binds heparin normally.


.0012   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

SERPINC1, PRO41LEU
SNP: rs121909551, gnomAD: rs121909551, ClinVar: RCV000019627, RCV001090508

This variant, formerly titled THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY, has been reclassified because its contribution to the phenotype has not been confirmed.

AT-III Clichy, a substitution of leucine for proline-41, was described by Chang and Tran (1986), Aiach et al. (1987), and Molho-Sabatier et al. (1989). The variant has also been called AT-III Clichy-2, AT-III Basel, AT-III Franconville.

Aiach et al. (1987) found the mutation in heterozygous state in a 24-year-old woman presenting with a thoracic outlet syndrome.

Perry and Carrell (1989) described the same substitution in this heparin-binding mutation, which was caused by a CGT-to-CAT change in exon 2.

Olds et al. (1990) noted that this mutation occurs within a CG dinucleotide, a recognized hotspot for single base mutations.

In a woman referred for routine prepregnancy testing and in several members of her family, de Roux et al. (1990) found heterozygosity for the pro41-to-leu mutation. None had had thrombotic complications. Testing of the properties of the mutant AT-III suggested that proline-41 is more involved in the molecular changes induced by heparin than in the primary binding of the activator.


.0013   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, VAL-3GLU
SNP: rs2227624, gnomAD: rs2227624, ClinVar: RCV000019628, RCV000852239, RCV000852240, RCV000857628

AT-III Dublin was described by Daly et al. (1987) in heterozygous state in 3 Irish individuals with no evidence of hypercoagulation-related problems. In the course of sequencing the AT3 gene in an AT-III Dublin heterozygote, Daly et al. (1990) identified a valine-to-glutamic acid substitution at position -3 in the signal peptide. A second, unrelated individual being investigated for recurrent thromboses was found to be heterozygous for same mutation. N-terminal sequencing of the antithrombin protein from both heterozygotes showed a truncated antithrombin in which the N-terminal dipeptide is absent. Daly et al. (1990) proposed that the prepeptide mutation redirects signal peptidase cleavage to a site 2 amino acids downstream into the mature protein.

Durr et al. (1992) found this mutation in southwest Germans and Portuguese, with frequencies of 0.007 and 0.00024, respectively.


.0014   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1
ClinVar: RCV000019629

Grau et al. (1988) described a quantitative and qualitative defect of AT-III in 4 members of a Spanish family with a thrombotic tendency (613118). The authors referred to the variant as AT-III Barcelona.


.0015   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47HIS
SNP: rs121909552, gnomAD: rs121909552, ClinVar: RCV000019630, RCV002054451

Owen et al. (1987) described this heparin-binding defect (AT-III Rouen I), a substitution of histidine at arginine-47 (R47H). Perry and Carrell (1989) found the same substitution, caused by a CCG-to-CTG change in exon 2.

Caso et al. (1990) identified the same mutation, which they called antithrombin Padua I, in several members of a family. No pathologic consequence (i.e., thrombosis) appeared to be associated with the mutation in this family. Caso et al. (1990) stated that the substitution resulted from a change of CGT to CAT in exon 2.

Emmerich et al. (1994) reported 2 brothers with AT-III deficiency (613118) and thromboembolic events who were compound heterozygous for 2 mutations in the AT3 gene: R47H, inherited from the mother, and a 9-bp deletion (107300.0050), probably inherited from the father, who had died from a pulmonary embolism at age 68. The 9-bp deletion results in a substitution of val426 by ala, a deletion of the tripeptide ala427-asn428-pro429, and a shift of the cys430 to position 427, which probably impairs the formation of the last disulfide bond.


.0016   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG47SER
SNP: rs121909547, gnomAD: rs121909547, ClinVar: RCV000019631

Borg et al. (1988) identified heterozygosity for an arg47-to-ser (R47S) substitution in the AT3 gene in a 40-year-old man who was admitted to hospital with a sudden myocardial infarction that lacked extensive coronary artery disease. His 13-year-old daughter displayed the same antithrombin abnormality. The variant, designated AT-III Rouen II, showed defective heparin and heparan sulfate activities. There was no definite family history of thrombosis.


.0017   MOVED TO 107300.0003


.0018   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393CYS
SNP: rs121909554, gnomAD: rs121909554, ClinVar: RCV000019632

In a 47-year-old patient presenting with recurrent venous thromboembolism (613118), Aiach et al. (1988) identified a reactive site variant, AT-III Avranches, in the AT3 gene that changed arginine-393 to cysteine. They identified the same abnormality with defective serine-protease inhibition in 2 of the patient's relatives.


.0019   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, PRO407LEU
SNP: rs121909555, ClinVar: RCV000019633

In affected members of a family from Utah with antithrombin III deficiency and thrombosis (613118) (Bock et al., 1985), Bock et al. (1988) identified heterozygosity for a substitution of leucine for proline-407 in the AT3 gene. AT-III Utah results in type I deficiency; antithrombin III shows a 50% decrease in both the immunologic and the functional assay.


.0020   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393CYS
ClinVar: RCV000019632

AT-III Northwick Park, described by Lane et al. (1987), was shown by Erdjument et al. (1988) to have substitution of cysteine for arginine-393. The same substitution was found by Erdjument et al. (1988) in AT-III Milano-1. The mutation leads to thrombosis (613118).


.0021   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG393HIS
SNP: rs121909549, gnomAD: rs121909549, ClinVar: RCV000019635

AT-III Glasgow, described by Lane et al. (1987), was shown by Erdjument et al. (1988) and by Owen et al. (1988) to have substitution of histidine for arginine-393 and to lead to thrombosis (613118).

Lane et al. (1989) showed that AT-III Sheffield has the same substitution. Owen et al. (1988) also demonstrated replacement of arginine by histidine at residue 393 in a 41-year-old male with a history of thrombotic events. Arginine-393 is located in the site involved in interaction with thrombin; the susceptibility to thrombosis with this mutation is thus explained. Molho-Sabatier et al. (1989) also found the arg393-to-his mutation in a variant form of AT-III.

AT-III Chicago, a functionally inactive antithrombin III associated with thrombotic disease, was found by Erdjument et al. (1989) to have the same substitution.


.0022   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA382THR
SNP: rs121909557, ClinVar: RCV000019636

In a French-Canadian family, Devraj-Kizuk et al. (1988) demonstrated a structural mutant of AT-III with defective serine protease activity, which they termed AT-III Hamilton. The propositus, a 54-year-old man with a history of recurrent thromboembolic events (613118), and his 2 asymptomatic adult children were heterozygous. Exon 6 showed a G-to-A point mutation in the first base of codon 382, leading to the substitution of threonine for alanine. Alanine-382, 12 residues from the reactive center of the enzyme, is a highly conserved amino acid in the family of serine protease inhibitors known as the serpins. In this reactive site mutation, Perry and Carrell (1989) found substitution of threonine for alanine-382 as a consequence of a GCA-to-ACA change in exon 6.


.0023   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ILE7ASN
SNP: rs121909558, ClinVar: RCV000019637

Brennan et al. (1988) demonstrated a substitution of asparagine for isoleucine at position 7 in a mutant antithrombin III, designated AT-III Rouen III, isolated from the plasma of a patient with pulmonary embolism (613118). The mutation introduced a new asn-cys-thr glycosylation sequence. The new oligosaccharide attachment site occupied the base of the presumed heparin-binding site, and the finding explained the consequent decrease in heparin affinity. Perry and Carrell (1989) also found this substitution, which was due to an ATC-to-AAC change, as the basis of a molecule defective in heparin binding.


.0024   MOVED TO 107300.0012


.0025   MOVED TO 107300.0003


.0026   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG24CYS
SNP: rs28929469, gnomAD: rs28929469, ClinVar: RCV000019638, RCV000420779

In a 25-year-old man who unexpectedly developed coronary thrombosis (613118), Borg et al. (1990) identified heterozygosity for a CGC-to-TGC transition at nucleotide 166 in exon 2 of the AT3 gene, resulting in an arg24-to-cys substitution. He inherited the mutation from his asymptomatic father. He inherited a hypofibrinogenemia from his mother. The AT3 mutation, designated AT-III Rouen IV, results in impaired heparin binding.


.0027   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA384SER
SNP: rs121909548, gnomAD: rs121909548, ClinVar: RCV000019639, RCV000249153, RCV000857698, RCV001270536

Harper et al. (1991) identified AT-III Cambridge II, which has a substitution of serine for alanine-384. This mutation occurs at the same codon as AT-III Cambridge I (107300.0007). Perry et al. (1991) identified 4 unrelated persons with an identical antithrombin variant, associated in one of them with episodes of recurrent venous thromboses (613118). In each case, the plasma antithrombin concentration was normal and the only functional abnormality was a minor but consistent decrease in the heparin-induced thrombin inhibition, suggesting a mutation at or near the reactive center of the molecule. Amplification and direct sequencing of exon 6 showed a G-to-T mutation at nucleotide 1246, which corresponded to a substitution of serine for alanine at residue 384.


.0028   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP DEL, A
SNP: rs1572088775, ClinVar: RCV000851895

Grundy et al. (1991) identified 2 patients, each from unrelated families segregating AT-III deficiency and a history of thrombosis (613118), who were heterozygous for different frameshift mutations involving the same GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a heterozygous deletion of the A nucleotide, whereas the second had a heterozygous deletion of an A and a G (107300.0029). Grundy et al. (1991) pointed out that the deletion-prone glu245 codon is located within a GAGAG motif that is effectively a short overlapping direct repeat. In addition, a short inverted repeat flanked the site of deletion. They pointed to similar deletion hotspots in the F8, HPRT, HBA2, and HBB genes and pointed out common characteristics of these hotspots.


.0029   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 2-BP DEL, AG
SNP: rs1657694750, ClinVar: RCV001235412

Grundy et al. (1991) identified 2 patients, each from unrelated families segregating AT-III deficiency and a history of thrombosis (613118), who were heterozygous for different frameshift mutations involving the same GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a heterozygous deletion of the A nucleotide (107300.0028), whereas the second had a heterozygous deletion of an A and a G. Grundy et al. (1991) pointed out that the deletion-prone glu245 codon is located within a GAGAG motif that is effectively a short overlapping direct repeat. In addition, a short inverted repeat flanked the site of deletion. They pointed to similar deletion hotspots in the F8, HPRT, HBA2, and HBB genes and pointed out common characteristics of these hotspots.


.0030   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, 780A
SNP: rs1572088837, ClinVar: RCV000019642

In a woman who developed pulmonary embolism during the postpartum period of her first delivery and has AT-III deficiency (613118), Vidaud et al. (1991) identified heterozygosity for an insertion of an adenine at position 780 of the AT3 gene, according to the cDNA numbering of Chandra et al. (1983). The mutation generated a frameshift that modified the amino acid sequence and introduced a premature stop codon at position 232 of the protein. The woman's mother, who also had AT-III deficiency and reported a history of recurrent venous thrombosis, was heterozygous for the mutation.


.0031   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER291PRO
SNP: rs121909560, ClinVar: RCV000019643

In a woman with type I AT-III deficiency who experienced several deep vein thromboses (613118), Vidaud et al. (1991) identified heterozygosity for a 2-bp deletion at positions 965 and 966 or at 967 and 968. (Because 2 AG dinucleotides were located next to each other, it was impossible to tell which of the 2 was deleted.) The deletion created a new reading frame from lysine-290 on, converting ser291 to proline and introducing a stop codon at position 309 in the protein sequence. Her 2 children were also heterozygous for the mutation and had decreased AT-III levels.


.0032   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASP309LYS
SNP: rs121909561, ClinVar: RCV000019644

In a 48-year-old man with type I antithrombin III deficiency and a history of thrombotic events (613118), Vidaud et al. (1991) found heterozygosity for a 4-bp deletion in the AT3 gene, resulting in a new reading frame beyond leu308, changing aspartic acid-309 to lysine and resulting in a TGA stop codon at amino acid position 313. One of his sons, who was then 35 years old, was heterozygous for the mutation and had AT-III deficiency but was free of thrombotic events.


.0033   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG129TER
SNP: rs121909562, ClinVar: RCV000019645, RCV001588819

In 3 patients from 2 apparently unrelated families with thrombophilia due to type Ia AT-III deficiency (613118), Gandrille et al. (1991) identified a heterozygous C-to-T mutation at codon 129 of the AT3 gene, resulting in change from arginine to stop. Olds et al. (1991) reported 4 further kindreds in which the same mutation was associated with type Ia AT-III deficiency and thrombotic disease. They stated that this mutation was present in about 10% of their families with type Ia. (Type Ia is characterized by the presence of only half the normal AT-III concentration in plasma, with no detectable variant protein.) The mutation in AT-III Geneva (107300.0034) occurs at the same codon.


.0034   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ARG129GLN
SNP: rs121909563, gnomAD: rs121909563, ClinVar: RCV000019646

In a patient with type Ia deficiency of antithrombin III who had 1 episode of pulmonary embolism (613118), Gandrille et al. (1990) identified heterozygosity for a G-A transition in the AT3 gene, resulting in substitution of glutamine for arginine-129. The finding of mutations at arginine-129 indicates its importance to the heparin-binding site of AT3. The mutation was designated AT-III Geneva.


.0035   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, PRO429LEU
SNP: rs121909564, ClinVar: RCV000019647

AT-III Budapest was the first type 2a AT-III variant described (Sas et al. (1974, 1975, 1978)). The propositus and several members of the kindred had had thromboembolic episodes (613118). The parents of the propositus were consanguineous.

Olds et al. (1992) showed that the AT-III Budapest allele, for which the propositus was homozygous, contained a single nucleotide substitution leading to the replacement of proline by leucine at codon 429. Proline at this position is highly conserved across the whole of the serpin family of proteins.


.0036   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER349PRO
SNP: rs121909565, ClinVar: RCV000019648

In affected members of an English family segregating recurrent venous thrombosis (613118), Grundy et al. (1992) identified heterozygosity for a point mutation in exon 4 of the AT3 gene, resulting in substitution of proline for serine-349.


.0037   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, GLY392ASP
SNP: rs121909566, ClinVar: RCV000019649

Antithrombin III Stockholm, found in a woman who developed a pulmonary embolus (613118) while on oral contraceptives at age 19, was shown by Blajchman et al. (1992) to have a substitution of aspartic acid for glycine-392, resulting from a G-to-A change in the second base of codon 392.


.0038   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, LEU99PHE
SNP: rs121909567, gnomAD: rs121909567, ClinVar: RCV000019650, RCV000851769, RCV001543498

Olds et al. (1992) described a CTC-to-TTC transition at codon 99 of the AT3 gene, altering the normal leucine to phenylalanine. The proband had a history of venous thrombotic disease (613118) and was found to be homozygous for the mutation. The variant protein showed reduced heparin affinity and reduced antiproteinase activity in the presence of either unfractionated heparin or the AT-binding heparin pentasaccharide, when compared to normal AT. The substitution is located near the proposed heparin-binding site.


.0039   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, T, CODON 48
SNP: rs2102789885, ClinVar: RCV000019651

In a patient with antithrombin III deficiency and a proven family history of thromboembolic disease (613118), Daly et al. (1992) identified heterozygosity for a 1-bp insertion (T) in exon 2 of the AT3 gene, causing a frameshift at codon 48 from a valine (GTC) to a cysteine (TGT) and a premature stop codon at position 72. A truncated AT3 protein could not be detected in plasma, suggesting that it failed to be secreted or was rapidly degraded. The mutation was designated AT48(+T).


.0040   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP INS, A, CODON 208
SNP: rs2102784614, ClinVar: RCV000019652

Daly et al. (1992) studied a 37-year-old woman with antithrombin III deficiency and a proven family history of thromboembolic disease (613118). Using PCR and direct sequencing of amplified DNA, they identified an insertion of an A in exon 3B of the AT3 gene, changing codon 208 from AAT (asparagine) to AAA (lysine) and creating a frameshift with a stop codon at position 209. No abnormal AT3 was detected in the plasma. The mutation was designated AT208(+A).


.0041   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 1-BP DEL, A, CODON 370
SNP: rs2102778876, ClinVar: RCV000019653

Daly et al. (1992) studied a 24-year-old woman with antithrombin III deficiency and a history of thromboembolic disease (613118). Using PCR and direct sequencing of amplified DNA, they identified a deletion of an A in codon 370 in exon 5 of the AT3 gene, changing AAG (lysine) to AGG (arginine) and resulting in a frameshift with a stop codon at position 375. No abnormal antithrombin protein was detected in the plasma. The mutation was designated AT370(-A).


.0042   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ALA387VAL
SNP: rs121909568, gnomAD: rs121909568, ClinVar: RCV000019654

In a patient with recurrent venous thrombosis and an AT-III activity/antigen level consistent with type I AT-III deficiency (613118), White et al. (1992) identified heterozygosity for a C-T transition in the AT3 gene, resulting in an ala387-to-val substitution near the reactive site.


.0043   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER116PRO
SNP: rs121909569, gnomAD: rs121909569, ClinVar: RCV000019655

In a 33-year-old man who had recurrent cerebral infarctions (613118), Okajima et al. (1993) found a T-to-C transition in exon 3a which resulted in the substitution of proline for serine at codon 116. The patient was heterozygous for the mutation, which lacked affinity for heparin. The variant was designated AT-III Nagasaki.


.0044   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, LEU-10PRO
SNP: rs387906575, ClinVar: RCV000019656

Most secretory proteins, including antithrombin, are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). Fitches et al. (1998) identified a novel mutation, which affected the central hydrophobic domain of the AT3 signal peptide, in a proband presenting with venous thrombotic disease and type I AT3 deficiency (613118). The mutation was a 2436T-C transition, resulting in a leucine to proline change at the -10 residue of the signal peptide. Fitches et al. (1998) investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT3 cDNAs with mutations affecting the -10 residue. Glycosylated AT3 was secreted from COS-7 cells transfected with wildtype AT3, -10leu deletion, -10val or -10met variants, but not variants with pro, thr, arg, or gly at -10. Cell-free expression of wildtype and variant AT3 cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for the ER. Variant AT3 proteins with pro, thr, arg, or gly at residue -10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested that they had not been translocated into microsomes. The results suggested that the ability of AT3 signal peptide to direct the protein to the ER for cotranslational processing events is critically dependent on maintaining the hydrophobic nature of the region including residue -10. The investigations defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT3 deficiency.


.0045   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASN135THR
SNP: rs121909570, ClinVar: RCV000019657

In a 25-year-old Italian woman who had experienced no thrombosis and had no family history of venous thrombosis, Bayston et al. (1999) found antithrombin deficiency (613118) with borderline levels (approximately 70% antigen and activity) of antithrombin. Direct sequencing of amplified DNA showed a mutation in codon 135, AAC to ACC, predicting a heterozygous asn135-to-thr substitution. This substitution altered the predicted consensus sequence for glycosylation, asn-X-ser, adjacent to the heparin interaction site of antithrombin. Antithrombin isolated from plasma of the patient by heparin-Sepharose chromatography contained amounts of beta-antithrombin (the very high affinity fraction) greatly increased (approximately 20 to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wildtype and variant protein were translated and then exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represented a novel cause of antithrombin deficiency, removal of glycosylation consensus sequence, and highlighted the potentially important role of beta-antithrombin in regulating coagulation.


.0046   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, ASN187ASP
SNP: rs121909571, gnomAD: rs121909571, ClinVar: RCV000019658

Bruce et al. (1994) described thromboembolic disease due to thermolabile conformational changes of AT-III Rouen VI (613118), which carries an asn187-to-asp missense mutation in the AT3 gene.


.0047   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, SER191PRO
SNP: rs121909572, ClinVar: RCV000019659

Baud et al. (2001) reported a neonate who died from a fatal cerebral hemorrhage involving the left thalamus following deep cerebral vein thrombosis (613118). The child was heterozygous for a 6472T-C transition in the AT3 gene, resulting in a serine-to-proline substitution at codon 191 (S191P). Antithrombin levels were in the low normal range. An asymptomatic sister, mother, and maternal grandfather had the same mutation. A maternal aunt had suffered an undiagnosed pulmonary embolism presumably secondary to antithrombin III deficiency.


.0048   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, CYS95ARG
SNP: rs121909573, ClinVar: RCV000019660

Ozawa et al. (1997) described antithrombin III deficiency (613118) caused by a T-to-C transition in the AT3 gene, resulting in a cys95-to-arg (C95R) substitution. Because this cysteine is responsible for the forming of an intramolecular disulfide bond, the mutation ostensibly affects the folding of AT3 molecules. Tanaka et al. (2002) transfected Chinese hamster ovary cells with the cDNA of AT-III Morioka and compared its intracellular fate to that of wildtype AT-III. They found that the mutant AT-III is not transported to the Golgi apparatus and accumulates without degradation in novel structures surrounded by a single membrane derived from the endoplasmic reticulum.


.0049   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 3-BP DEL
SNP: rs2102773181, ClinVar: RCV000019661

In a proband with early-onset thrombosis and antithrombin III deficiency (613118), Raja et al. (2003) identified a heterozygous 3-bp deletion corresponding to the codon for the P1 arginine-393 residue (ARG393DEL). The mutation abolished inhibitor activity toward thrombin and factor Xa, but bound to either full-length or pentasaccharide heparins with substantially higher affinity than that of the normal inhibitor. The authors suggested that the unusually severe thrombosis associated with this mutation may be explained by the ability of antithrombin London to bind endogenous heparan sulfate or heparan molecules and to thereby block activation of the normal inhibitor.


.0050   THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY

SERPINC1, 9-BP DEL, NT13395
SNP: rs2102772927, ClinVar: RCV000019662

For discussion of the 9-bp deletion in the SERPINC1 gene that was found in compound heterozygous state in 2 brothers with antithrombin III deficiency (613118) by Emmerich et al., 1994, see 107300.0015.


See Also:

Bauer et al. (1985); Beukes and Heyns (1980); Blajchman et al. (1992); Brenner et al. (1988); Carvalho and Ellman (1976); Cosgriff et al. (1983); Egeberg (1965); Erdjument et al. (1988); Filip et al. (1976); Gallus (1984); Griffith et al. (1983); Gruenberg et al. (1975); Gyde et al. (1978); Halal et al. (1983); Hofman et al. (1980); Knot et al. (1986); Laharrague et al. (1980); Lane et al. (1989); Lane et al. (1987); Leone et al. (1983); Leone et al. (1980); Magenis et al. (1978); Mannucci et al. (1982); Manotti et al. (1982); Matsuo et al. (1979); Mohanty et al. (1982); Odegard and Abildgaard (1977); Peterson and Blackburn (1985); Pitney et al. (1980); Prochownik (1985); Scully et al. (1981); Shapiro et al. (1981); Stathakis et al. (1977); Tengborn et al. (1985); Towne et al. (1981); Vomberg et al. (1987); Williams and Murano (1981); Winter et al. (1982)

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Contributors:
Carol A. Bocchini - updated : 11/17/2009
Ada Hamosh - updated : 4/15/2003
Ada Hamosh - updated : 1/25/2002
Victor A. McKusick - updated : 2/28/2001
Victor A. McKusick - updated : 1/19/2000
Ada Hamosh - updated : 9/15/1999
Victor A. McKusick - updated : 2/1/1999

Creation Date:
Victor A. McKusick : 6/16/1986

Edit History:
carol : 03/29/2022
carol : 09/06/2017
carol : 07/18/2016
carol : 7/14/2016
joanna : 7/13/2016
mcolton : 8/19/2015
carol : 7/23/2015
carol : 2/10/2015
mcolton : 2/6/2015
terry : 11/29/2012
terry : 7/27/2012
joanna : 4/30/2012
carol : 3/1/2012
carol : 6/22/2011
carol : 4/8/2011
carol : 6/30/2010
terry : 1/21/2010
terry : 12/1/2009
carol : 11/19/2009
carol : 11/18/2009
carol : 11/17/2009
terry : 11/16/2009
terry : 11/16/2009
carol : 11/13/2009
terry : 6/3/2009
joanna : 3/17/2004
alopez : 4/17/2003
terry : 4/15/2003
alopez : 5/2/2002
terry : 3/13/2002
alopez : 1/30/2002
terry : 1/25/2002
terry : 3/26/2001
alopez : 3/1/2001
terry : 2/28/2001
terry : 12/5/2000
mcapotos : 1/24/2000
terry : 1/19/2000
carol : 9/17/1999
terry : 9/15/1999
terry : 4/30/1999
carol : 2/15/1999
terry : 2/1/1999
dkim : 7/21/1998
dkim : 6/30/1998
alopez : 5/14/1998
mark : 7/16/1997
alopez : 7/16/1997
alopez : 7/16/1997
mark : 12/26/1996
terry : 11/12/1996
mark : 1/30/1996
mark : 1/24/1996
terry : 12/22/1994
jason : 7/1/1994
mimadm : 3/28/1994
carol : 2/23/1994
carol : 7/9/1993
carol : 6/3/1993