* 142360

HEPARIN COFACTOR II; HCF2


Alternative titles; symbols

LEUSERPIN 2; LS2
SERPIND1


HGNC Approved Gene Symbol: SERPIND1

Cytogenetic location: 22q11.21     Genomic coordinates (GRCh38): 22:20,774,113-20,787,720 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
22q11.21 Thrombophilia 10 due to heparin cofactor II deficiency 612356 AD 3

TEXT

Description

Heparin cofactor II is a serine protease inhibitor in plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin (Kondo et al., 1996).


Cloning and Expression

From a human liver cDNA library, Ragg (1986) isolated a novel member of the protease inhibitor family. The inhibitor, named leuserpin-2, has 48 amino acids and contains a leucine residue at its putative reactive center. It shows about 25% to 28% homology to 3 human members of the plasma protease inhibitor family: antithrombin III (AT3; 107300), alpha-1-antitrypsin (PI; 107400), and alpha-1-antichymotrypsin (AACT; 107280). Comparison with published partial amino acid sequences suggested that LS2 is closely related or identical to heparin cofactor II.

Blinder et al. (1988) isolated an apparently full-length cDNA for HCF II from a human liver cDNA library.


Gene Structure

Herzog et al. (1991) determined that the HCF2 gene contains 5 exons.


Mapping

By blot hybridization of a probe to DNA isolated from sorted human chromosomes, Blinder et al. (1988) mapped the HCF2 gene to chromosome 22. By use of rodent-human somatic cell hybrids carrying only parts of human chromosome 22 and by study of a chronic myelogenous leukemia cell line, Herzog et al. (1991) localized the HCF2 gene to chromosome 22q11, proximal to the breakpoint cluster region (151410).


Gene Function

Aihara et al. (2004) measured plasma HCF II activity, HDL cholesterol level, and carotid artery plaque thickness in 306 Japanese individuals over 40 (mean age, 68.9 years) and observed that HCF II activity decreased with age. Multiple regression analysis revealed that plasma HCF II activity and HDL cholesterol level were independently associated with decreased plaque thickness and that the antiatherogenic contribution of HCF II activity was stronger than that of HDL cholesterol.


Molecular Genetics

Using crossed immunolectrophoresis, Andersson et al. (1987) were the first to demonstrate molecular heterogeneity of the HCF II molecule, the so-called 'Oslo variant,' in affected members of 2 Norwegian families with HCF II deficiency (612356). Their findings were consistent with an autosomal dominant pattern of inheritance; affected individuals had half the normal amount of normal HCF II and were presumed heterozygotes.

Using PCR, Blinder et al. (1989) amplified DNA fragments encoding the N-terminal 220 amino acids of HCF II from a patient with the Oslo variant. They identified a point mutation resulting in an arg189-to-his (R189H; 142360.0001) substitution in 1 allele. Blinder et al. (1989) created the same mutation in the cDNA of native HCF II by oligonucleotide-directed mutagenesis and expressed it in E. coli. The recombinant cofactor reacted with thrombin in the presence of heparin, but not dermatan sulfate, confirming that the R189H mutation is responsible for the functional abnormality in HCF II Oslo.


Animal Model

Vicente et al. (2007) reported that Hcf2 -/- mice are born at the expected mendelian frequency and that they appear normal and are fertile. However, Vicente et al. (2007) found that Hcf2 -/- mice were more sensitive than wildtype mice to neointima formation following mechanical dilation of the common carotid artery. Dermatan sulfate administered intravenously within 48 hours of injury inhibited neointima formation in wildtype mice, but it had no effect in Hcf2 -/- mice. In addition, Hcf2 deletion increased the size of diet-induced atherosclerotic lesions that developed in the aortic arch of ApoE (107741) -/- mice. Vicente et al. (2007) concluded that HCF2 deficiency promotes atherogenesis and neointima formation and that treatment with dermatan sulfate reduces neointima formation in an HCF2-dependent manner.


ALLELIC VARIANTS ( 4 Selected Examples):

.0001 HEPARIN COFACTOR II DEFICIENCY

SERPIND1, ARG189HIS
   RCV000016092

By means of the polymerase chain reaction (PCR), Blinder et al. (1989) amplified DNA fragments encoding the N-terminal 220 amino acid residues of heparin cofactor II from a patient with HCF II deficiency (612356) and the Oslo HCF II variant. A point mutation (G-to-A) resulting in substitution of his for arg189 was found in 1 allele. The same mutation was created in the cDNA of native heparin cofactor II by oligonucleotide-directed mutagenesis and was expressed in E. coli. The recombinant cofactor reacted with thrombin in the presence of heparin, but not dermatan sulfate, confirming that this mutation is responsible for the functional abnormality in HCF II Oslo.


.0002 HEPARIN COFACTOR II DEFICIENCY

SERPIND1, 1-BP INS, T, EXON 2
  
RCV000016093

Kondo et al. (1996) studied the defect in a Japanese patient with type I HCF II deficiency (612356) who suffered from angina pectoris and coronary artery disease. PCR-based sequence analysis showed that the patient's HCF2 gene had a 1-bp insertion, a T after the GAT codon for asp88 in exon 2, resulting in a frameshift. The abnormal HCF II Awaji protein was predicted to have an altered amino acid sequence from position 89 and to terminate at residue 107, thus being composed of the NH2-terminal one-fifth of normal HCF II and therefore dysfunctional for thrombin inhibition. The sister appeared to have the same mutation. Cellular studies suggested that the abnormal HCF II Awaji protein is secreted normally but rapidly degraded in the circulating blood.


.0003 THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY

SERPIND1, 2-BP DEL, 12896TT
  
RCV000016094

In 2 unrelated patients from the Rimini province in northern Italy with type I HCF II deficiency and thrombophilia (THPH10; 612356), Bernardi et al. (1996) identified heterozygosity for a 2-bp deletion (12896delTT) in exon 5 of the HCF2 gene, resulting in a frameshift at leu457 that elongates the protein by 4 amino acids. The variant was designated HCF II Rimini. In both probands, another hereditary thrombophilic alteration was diagnosed: the factor V Leiden mutation (R506Q; 612309.0001) was detected in 1 and type I protein C deficiency (176860) in the other. The tracing of the single defects in several unaffected members of each family indicated that the mutations clinically manifested only in the doubly heterozygous condition; the asymptomatic son of the proband with the HCF2 deletion and the factor V Leiden mutation was the only other double heterozygote detected.


.0004 THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY

SERPIND1, PRO443LEU
  
RCV000016095

In a 66-year-old Japanese woman with type I congenital HCF II deficiency and widespread atherosclerotic lesions (612356), Kanagawa et al. (2001) identified a heterozygous 12854C-T transition in exon 5 of the HCF2 gene, resulting in a pro443-to-leu (P443L) substitution. The variant, which was designated HCF II Tokushima, was found in 6 other family members with HCF II deficiency, but not in healthy unaffected individuals. Transfected COS-1 cells exhibited perinuclear immunohistochemical staining, indicating impaired secretion of the mutant HCF II molecules due to intracellular degradation.


REFERENCES

  1. Aihara, K., Azuma, H., Takamori, N., Kanagawa, Y., Akaike, M., Fujimura, M., Yoshida, T., Hashizume, S., Kato, M., Yamaguchi, H., Kato, S., Ikeda, Y., Arase, T., Kondo, A., Matsumoto, T. Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals. Circulation 109: 2761-2765, 2004. [PubMed: 15148272, related citations] [Full Text]

  2. Andersson, T. R., Larsen, M. L., Abildgaard, U. Low heparin cofactor II associated with abnormal crossed immunoelectrophoresis pattern in two Norwegian families. Thromb. Res. 47: 243-248, 1987. [PubMed: 2443998, related citations] [Full Text]

  3. Bernardi, F., Legnani, C., Micheletti, F., Lunghi, B., Ferraresi, P., Palareti, G., Biagi, R., Marchetti, G. A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb. Haemost. 76: 505-509, 1996. [PubMed: 8902986, related citations]

  4. Blinder, M. A., Andersson, T. R., Abildgaard, U., Tollefsen, D. M. Heparin cofactor II(Oslo): mutation of arg-189-to-his decreases the affinity for dermatan sulfate. J. Biol. Chem. 264: 5128-5133, 1989. [PubMed: 2647747, related citations]

  5. Blinder, M. A., Marasa, J. C., Reynolds, C. H., Deaven, L. L., Tollefsen, D. M. Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli. Biochemistry 27: 752-759, 1988. [PubMed: 2894851, related citations] [Full Text]

  6. Herzog, R., Lutz, S., Blin, N., Marasa, J. C., Blinder, M. A., Tollefsen, D. M. Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11. Biochemistry 30: 1350-1357, 1991. [PubMed: 1671335, related citations] [Full Text]

  7. Kanagawa, Y., Shigekiyo, T., Aihara, K., Akaike, M., Azuma, H., Matsumoto, T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb. Haemost. 85: 101-107, 2001. [PubMed: 11204559, related citations]

  8. Kondo, S., Tokunaga, F., Kario, K., Matsuo, T., Koide, T. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). Blood 87: 1006-1012, 1996. [PubMed: 8562924, related citations]

  9. Ragg, H. A new member of the plasma protease inhibitor gene family. Nucleic Acids Res. 14: 1073-1088, 1986. [PubMed: 3003690, related citations] [Full Text]

  10. Vicente, C. P., He, L., Tollefsen, D. M. Accelerated atherogenesis and neointima formation in heparin cofactor II-deficient mice. Blood 110: 4261-4267, 2007. [PubMed: 17878401, images, related citations] [Full Text]


Patricia A. Hartz - updated : 10/23/2008
Marla J. F. O'Neill - updated : 1/31/2006
Marla J. F. O'Neill - updated : 5/16/2005
Victor A. McKusick - updated : 12/13/1999
Alan F. Scott - edited : 12/27/1996
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 10/07/2014
carol : 3/1/2012
carol : 2/28/2012
carol : 11/19/2009
mgross : 10/23/2008
mgross : 10/23/2008
carol : 10/8/2008
wwang : 2/3/2006
terry : 1/31/2006
wwang : 7/11/2005
wwang : 7/7/2005
terry : 5/16/2005
terry : 6/2/2004
joanna : 3/17/2004
terry : 3/13/2002
mcapotos : 12/17/1999
mcapotos : 12/16/1999
terry : 12/13/1999
mark : 12/27/1996
mark : 3/21/1996
terry : 3/13/1996
mimadm : 9/24/1994
carol : 10/9/1992
supermim : 3/16/1992
carol : 8/7/1991
supermim : 3/20/1990
ddp : 10/27/1989

* 142360

HEPARIN COFACTOR II; HCF2


Alternative titles; symbols

LEUSERPIN 2; LS2
SERPIND1


HGNC Approved Gene Symbol: SERPIND1

SNOMEDCT: 234468009;  


Cytogenetic location: 22q11.21     Genomic coordinates (GRCh38): 22:20,774,113-20,787,720 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
22q11.21 Thrombophilia 10 due to heparin cofactor II deficiency 612356 Autosomal dominant 3

TEXT

Description

Heparin cofactor II is a serine protease inhibitor in plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin (Kondo et al., 1996).


Cloning and Expression

From a human liver cDNA library, Ragg (1986) isolated a novel member of the protease inhibitor family. The inhibitor, named leuserpin-2, has 48 amino acids and contains a leucine residue at its putative reactive center. It shows about 25% to 28% homology to 3 human members of the plasma protease inhibitor family: antithrombin III (AT3; 107300), alpha-1-antitrypsin (PI; 107400), and alpha-1-antichymotrypsin (AACT; 107280). Comparison with published partial amino acid sequences suggested that LS2 is closely related or identical to heparin cofactor II.

Blinder et al. (1988) isolated an apparently full-length cDNA for HCF II from a human liver cDNA library.


Gene Structure

Herzog et al. (1991) determined that the HCF2 gene contains 5 exons.


Mapping

By blot hybridization of a probe to DNA isolated from sorted human chromosomes, Blinder et al. (1988) mapped the HCF2 gene to chromosome 22. By use of rodent-human somatic cell hybrids carrying only parts of human chromosome 22 and by study of a chronic myelogenous leukemia cell line, Herzog et al. (1991) localized the HCF2 gene to chromosome 22q11, proximal to the breakpoint cluster region (151410).


Gene Function

Aihara et al. (2004) measured plasma HCF II activity, HDL cholesterol level, and carotid artery plaque thickness in 306 Japanese individuals over 40 (mean age, 68.9 years) and observed that HCF II activity decreased with age. Multiple regression analysis revealed that plasma HCF II activity and HDL cholesterol level were independently associated with decreased plaque thickness and that the antiatherogenic contribution of HCF II activity was stronger than that of HDL cholesterol.


Molecular Genetics

Using crossed immunolectrophoresis, Andersson et al. (1987) were the first to demonstrate molecular heterogeneity of the HCF II molecule, the so-called 'Oslo variant,' in affected members of 2 Norwegian families with HCF II deficiency (612356). Their findings were consistent with an autosomal dominant pattern of inheritance; affected individuals had half the normal amount of normal HCF II and were presumed heterozygotes.

Using PCR, Blinder et al. (1989) amplified DNA fragments encoding the N-terminal 220 amino acids of HCF II from a patient with the Oslo variant. They identified a point mutation resulting in an arg189-to-his (R189H; 142360.0001) substitution in 1 allele. Blinder et al. (1989) created the same mutation in the cDNA of native HCF II by oligonucleotide-directed mutagenesis and expressed it in E. coli. The recombinant cofactor reacted with thrombin in the presence of heparin, but not dermatan sulfate, confirming that the R189H mutation is responsible for the functional abnormality in HCF II Oslo.


Animal Model

Vicente et al. (2007) reported that Hcf2 -/- mice are born at the expected mendelian frequency and that they appear normal and are fertile. However, Vicente et al. (2007) found that Hcf2 -/- mice were more sensitive than wildtype mice to neointima formation following mechanical dilation of the common carotid artery. Dermatan sulfate administered intravenously within 48 hours of injury inhibited neointima formation in wildtype mice, but it had no effect in Hcf2 -/- mice. In addition, Hcf2 deletion increased the size of diet-induced atherosclerotic lesions that developed in the aortic arch of ApoE (107741) -/- mice. Vicente et al. (2007) concluded that HCF2 deficiency promotes atherogenesis and neointima formation and that treatment with dermatan sulfate reduces neointima formation in an HCF2-dependent manner.


ALLELIC VARIANTS 4 Selected Examples):

.0001   HEPARIN COFACTOR II DEFICIENCY

SERPIND1, ARG189HIS
SNP: rs5907, gnomAD: rs5907, ClinVar: RCV000016092

By means of the polymerase chain reaction (PCR), Blinder et al. (1989) amplified DNA fragments encoding the N-terminal 220 amino acid residues of heparin cofactor II from a patient with HCF II deficiency (612356) and the Oslo HCF II variant. A point mutation (G-to-A) resulting in substitution of his for arg189 was found in 1 allele. The same mutation was created in the cDNA of native heparin cofactor II by oligonucleotide-directed mutagenesis and was expressed in E. coli. The recombinant cofactor reacted with thrombin in the presence of heparin, but not dermatan sulfate, confirming that this mutation is responsible for the functional abnormality in HCF II Oslo.


.0002   HEPARIN COFACTOR II DEFICIENCY

SERPIND1, 1-BP INS, T, EXON 2
SNP: rs587777759, ClinVar: RCV000016093

Kondo et al. (1996) studied the defect in a Japanese patient with type I HCF II deficiency (612356) who suffered from angina pectoris and coronary artery disease. PCR-based sequence analysis showed that the patient's HCF2 gene had a 1-bp insertion, a T after the GAT codon for asp88 in exon 2, resulting in a frameshift. The abnormal HCF II Awaji protein was predicted to have an altered amino acid sequence from position 89 and to terminate at residue 107, thus being composed of the NH2-terminal one-fifth of normal HCF II and therefore dysfunctional for thrombin inhibition. The sister appeared to have the same mutation. Cellular studies suggested that the abnormal HCF II Awaji protein is secreted normally but rapidly degraded in the circulating blood.


.0003   THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY

SERPIND1, 2-BP DEL, 12896TT
SNP: rs587777760, ClinVar: RCV000016094

In 2 unrelated patients from the Rimini province in northern Italy with type I HCF II deficiency and thrombophilia (THPH10; 612356), Bernardi et al. (1996) identified heterozygosity for a 2-bp deletion (12896delTT) in exon 5 of the HCF2 gene, resulting in a frameshift at leu457 that elongates the protein by 4 amino acids. The variant was designated HCF II Rimini. In both probands, another hereditary thrombophilic alteration was diagnosed: the factor V Leiden mutation (R506Q; 612309.0001) was detected in 1 and type I protein C deficiency (176860) in the other. The tracing of the single defects in several unaffected members of each family indicated that the mutations clinically manifested only in the doubly heterozygous condition; the asymptomatic son of the proband with the HCF2 deletion and the factor V Leiden mutation was the only other double heterozygote detected.


.0004   THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY

SERPIND1, PRO443LEU
SNP: rs121912420, ClinVar: RCV000016095

In a 66-year-old Japanese woman with type I congenital HCF II deficiency and widespread atherosclerotic lesions (612356), Kanagawa et al. (2001) identified a heterozygous 12854C-T transition in exon 5 of the HCF2 gene, resulting in a pro443-to-leu (P443L) substitution. The variant, which was designated HCF II Tokushima, was found in 6 other family members with HCF II deficiency, but not in healthy unaffected individuals. Transfected COS-1 cells exhibited perinuclear immunohistochemical staining, indicating impaired secretion of the mutant HCF II molecules due to intracellular degradation.


REFERENCES

  1. Aihara, K., Azuma, H., Takamori, N., Kanagawa, Y., Akaike, M., Fujimura, M., Yoshida, T., Hashizume, S., Kato, M., Yamaguchi, H., Kato, S., Ikeda, Y., Arase, T., Kondo, A., Matsumoto, T. Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals. Circulation 109: 2761-2765, 2004. [PubMed: 15148272] [Full Text: https://doi.org/10.1161/01.CIR.0000129968.46095.F3]

  2. Andersson, T. R., Larsen, M. L., Abildgaard, U. Low heparin cofactor II associated with abnormal crossed immunoelectrophoresis pattern in two Norwegian families. Thromb. Res. 47: 243-248, 1987. [PubMed: 2443998] [Full Text: https://doi.org/10.1016/0049-3848(87)90381-1]

  3. Bernardi, F., Legnani, C., Micheletti, F., Lunghi, B., Ferraresi, P., Palareti, G., Biagi, R., Marchetti, G. A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb. Haemost. 76: 505-509, 1996. [PubMed: 8902986]

  4. Blinder, M. A., Andersson, T. R., Abildgaard, U., Tollefsen, D. M. Heparin cofactor II(Oslo): mutation of arg-189-to-his decreases the affinity for dermatan sulfate. J. Biol. Chem. 264: 5128-5133, 1989. [PubMed: 2647747]

  5. Blinder, M. A., Marasa, J. C., Reynolds, C. H., Deaven, L. L., Tollefsen, D. M. Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli. Biochemistry 27: 752-759, 1988. [PubMed: 2894851] [Full Text: https://doi.org/10.1021/bi00402a039]

  6. Herzog, R., Lutz, S., Blin, N., Marasa, J. C., Blinder, M. A., Tollefsen, D. M. Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11. Biochemistry 30: 1350-1357, 1991. [PubMed: 1671335] [Full Text: https://doi.org/10.1021/bi00219a027]

  7. Kanagawa, Y., Shigekiyo, T., Aihara, K., Akaike, M., Azuma, H., Matsumoto, T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb. Haemost. 85: 101-107, 2001. [PubMed: 11204559]

  8. Kondo, S., Tokunaga, F., Kario, K., Matsuo, T., Koide, T. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). Blood 87: 1006-1012, 1996. [PubMed: 8562924]

  9. Ragg, H. A new member of the plasma protease inhibitor gene family. Nucleic Acids Res. 14: 1073-1088, 1986. [PubMed: 3003690] [Full Text: https://doi.org/10.1093/nar/14.2.1073]

  10. Vicente, C. P., He, L., Tollefsen, D. M. Accelerated atherogenesis and neointima formation in heparin cofactor II-deficient mice. Blood 110: 4261-4267, 2007. [PubMed: 17878401] [Full Text: https://doi.org/10.1182/blood-2007-04-086611]


Contributors:
Patricia A. Hartz - updated : 10/23/2008
Marla J. F. O'Neill - updated : 1/31/2006
Marla J. F. O'Neill - updated : 5/16/2005
Victor A. McKusick - updated : 12/13/1999
Alan F. Scott - edited : 12/27/1996

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
carol : 10/07/2014
carol : 3/1/2012
carol : 2/28/2012
carol : 11/19/2009
mgross : 10/23/2008
mgross : 10/23/2008
carol : 10/8/2008
wwang : 2/3/2006
terry : 1/31/2006
wwang : 7/11/2005
wwang : 7/7/2005
terry : 5/16/2005
terry : 6/2/2004
joanna : 3/17/2004
terry : 3/13/2002
mcapotos : 12/17/1999
mcapotos : 12/16/1999
terry : 12/13/1999
mark : 12/27/1996
mark : 3/21/1996
terry : 3/13/1996
mimadm : 9/24/1994
carol : 10/9/1992
supermim : 3/16/1992
carol : 8/7/1991
supermim : 3/20/1990
ddp : 10/27/1989