* 120328

COLLAGEN, TYPE XVIII, ALPHA-1; COL18A1


Other entities represented in this entry:

ENDOSTATIN, INCLUDED

HGNC Approved Gene Symbol: COL18A1

Cytogenetic location: 21q22.3     Genomic coordinates (GRCh38): 21:45,405,165-45,513,720 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.3 Glaucoma, primary closed-angle 618880 AD 3
Knobloch syndrome, type 1 267750 AR 3

TEXT

Cloning and Expression

Oh et al. (1994) isolated overlapping mouse cDNAs encoding a novel collagenous polypeptide, alpha-1(XVIII) collagen. Nucleotide sequence analysis showed that the COL18A1 gene contains 10 triple-helical domains separated and flanked by nontriple-helical regions. Within the nontriple-helical regions, there are several ser-gly-containing sequences that conform to the consensus sequences for glycosaminoglycan attachment sites in proteoglycan core proteins. Northern blot analysis detected COL18A1 transcripts in multiple organs, with the highest levels in liver, lung, and kidney.

Oh et al. (1994) reported the isolation of human cDNAs and genomic DNAs representing the COL18A1 gene.

Several lines of direct evidence show that angiogenesis is essential for the growth and persistence of solid tumors and metastases. To stimulate angiogenesis, tumors upregulate a variety of angiogenic factors. Many malignant tumors, however, also generate inhibitors of angiogenesis, including angiostatin. O'Reilly et al. (1994) discovered an angiogenesis inhibitor, designated angiostatin, that specifically inhibits endothelial cell proliferation. They showed that angiostatin is an internal fragment of plasminogen, containing at least 3 of the kringles of plasminogen. Using a rationale similar to that for the isolation of angiostatin, O'Reilly et al. (1997) isolated a 20-kD angiogenesis inhibitor, which they called endostatin, from a murine hemangioendothelioma. They found that endostatin is a C-terminal fragment of collagen XVIII. Systemic therapy with endostatin caused the nearly complete suppression of tumor-induced angiogenesis and strong antitumor activity.

Saarela et al. (1998) reported full-length human type XVIII collagen cDNAs that encode 2 variant chains of 1,516 and 1,336 residues. They found that the 2 chains have different signal peptides and N-terminal NC1 domains. The amino acid sequences of the human and previously characterized mouse alpha-1(XVIII) chains exhibited an overall identity of 79%. The highest homology between these chains was observed in their last 184 residues, corresponding to the proteolytic fragment endostatin.

Using immunohistochemical and expression analyses, Caglayan et al. (2014) identified COL18A1 expression in the pia and blood vessels of the developing human cerebral cortex, supporting a role for COL18A1 in human neurodevelopment.


Gene Structure

Rehn et al. (1996) showed that the mouse Col18a1 gene contains 43 exons spanning over 100 kb and that 2 alternative promoters are used. Promoter 1, which is about 50 kb upstream and adjacent to exons 1 and 2, produces a transcript that skips exon 3. Promoter 2, adjacent to exon 3, produces 2 types of transcripts depending on alternative splicing of that exon. All 3 predicted proteins differ in their amino-terminal noncollagenous domains.


Mapping

Using a genomic clone as a probe for fluorescence in situ hybridization, Oh et al. (1994) mapped the COL18A1 gene to 21q22.3. In addition, using an interspecific backcross panel, they showed that the murine Col18a1 is on chromosome 10, close to the Col6a1 and Col6a2 genes.


Gene Function

Upon comparison of COL18A1 sequences with those of COL15A1 (120325), Oh et al. (1994) observed a striking similarity in the lengths of the 6 most carboxyl-terminal triple-helical domains. In addition, within the carboxyl nontriple-helical domain NC1 of the 2 chains, a region of 177 amino acid residues showed about 60% identity. The similarities in structure suggested that the collagens are functionally related, and their distinct structure pointed to differences from other known collagen types. Oh et al. (1994) concluded that they belonged to a novel subfamily of extracellular matrix proteins with multiple triple-helical domains, and proposed to designate these as multiplexins, for 'protein with multiple triple-helix domains and interruptions.'

Based on mouse cDNA clones, Rehn and Pihlajaniemi (1994) likewise pointed out the homology between type XVIII and type XV collagens. Northern blot analysis demonstrated a striking tissue distribution for type XVIII collagen mRNAs, as the clones hybridized strongly with mRNAs of 4.3 and 5.3 kilobases that were present only in lung and liver of the 8 mouse tissues studied.

Endostatin is a potent antiangiogenic protein. Karumanchi et al. (2001) showed that alkaline phosphatase-tagged endostatin bound endothelial cells, revealing 2 binding affinities. Expression cloning identified the cell surface proteoglycan glypican, specifically glypican-1 (600395) or glypican-4 (300168), as the lower-affinity receptor. Biochemical and genetic studies indicated that the heparan sulfate glycosaminoglycans of glypican were critical for endostatin binding. Furthermore, endostatin selected a specific octasulfated hexasaccharide from a sequence in heparin. Karumanchi et al. (2001) also demonstrated a role for endostatin in renal tubular cell branching morphogenesis and showed that glypicans serve as low-affinity receptors for endostatin in these cells, as in endothelial cells. Antisense experiments suggested the critical importance of glypicans in mediating endostatin activities.

In humans, the COL18A1 gene encodes 2 distinct isoforms by use of 2 promoters, 1 of which is located upstream from exon 1 and the other of which is located upstream from exon 3 (Saarela et al., 1998). The 2 isoforms differ only at their signal peptides, with different N-terminal noncollagenous domains that are 303 or 493 residues in length.

Suzuki et al. (2002) showed that the longer human COL18A1 isoform, with 728 residues, is expressed in several tissues including the human eye. Lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but those patients who lack all forms present more severe ocular alterations.

Tumstatin and endostatin, 2 inhibitors of angiogenesis, derive from the precursor human collagen molecules COL4A3 (120070) and COL18A1, respectively. Although both of these inhibitors are NC1 domain fragments of collagens, they share only 14% amino acid homology. Sudhakar et al. (2003) evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these 2 collagen-derived inhibitors. Tumstatin prevents angiogenesis through inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas endostatin prevents endothelial cell migration with no effect on proliferation. Sudhakar et al. (2003) demonstrated that tumstatin binds to alpha-V-beta-3 integrin (193210, 173470) in a vitronectin/fibronectin/RGD cyclic peptide-independent manner, whereas endostatin competes with fibronectin/RGD cyclic peptide to bind alpha-5-beta-1 integrin (135620, 135630). The activity of tumstatin is mediated by alpha-V-beta-3 integrin, whereas the activity of endostatin is mediated by alpha-5-beta-1 integrin. Because of the distinct properties of tumstatin and endostatin, indicating their diverse antiangiogenic actions, the authors suggested the 2 be combined for targeting tumor angiogenesis.

By immunoprecipitation analysis using membrane fractions of human mammary epithelial cells, Shi et al. (2007) showed that endostatin specifically bound to cell surface nucleolin (NCL; 164035) with high affinity. Blockage of nucleolin with neutralizing antibody or knockdown of nucleolin by RNA interference countered the antiendothelial activity of endostatin and abrogated its antiangiogenic and antitumor activity in vivo. Nucleolin and endostatin colocalized on the cell surface of endothelial cells in tumors, and endostatin was internalized and transported into cell nuclei of endothelial cells via nucleolin. In the nucleus, phosphorylation of nucleolin, which is critical for cell proliferation, was inhibited by endostatin. Shi et al. (2007) concluded that nucleolin is an endostatin receptor that mediates the antiangiogenic and antitumor activities of endostatin.


Molecular Genetics

Knobloch Syndrome 1

Knobloch syndrome-1 (KNO1; 267750) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities, and occipital encephalocele. The KNO1 causative gene had been assigned to a 4.3-cM interval at 21q22.3 by linkage analysis in a large consanguineous Brazilian family. Sertie et al. (2000) narrowed the candidate interval to a region of less than 245 kb, which contained 24 expressed sequence tags, including the 5-prime end of the COL18A1 gene. They identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 (120328.0001) in 12 patients with Knobloch syndrome. Due to alternative splicing, the mutation creates a stop codon in exon 4, thus truncating the alpha-1(XVIII) collagen short form, which was otherwise expressed in human adult retina. The authors concluded that Knobloch syndrome-1 is caused by mutations in the COL18A1 gene, which may play a major role in retinal structure as well as in the closure of the neural tube.

Suzuki et al. (2002) screened the entire coding region and the exon-intron boundaries of the COL18A1 gene in 8 unrelated patients with Knobloch syndrome. Sixty different pathogenic changes were identified in alleles of 5 unrelated patients with KNO1 (3 compound heterozygotes and 2 homozygotes). All were truncating mutations leading to deficiency of 1 or all collagen XVIII isoforms and endostatin. A 2-bp mutation in exon 41 (120328.0002) was found in 3 unrelated individuals, each on a different haplotype, suggesting that this mutation had occurred more than once. Suzuki et al. (2002) found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms. None of the patients with mutations in the COL18A1 gene had any major kidney or liver defects, which was surprising because the 3 isoforms are highly expressed in these organs. The lack of collagen XVIII may be compensated by collagen XV (120325). Suzuki et al. (2002) suggested that predisposition to epilepsy might be due to abnormal neuronal migration. In 2 patients with Knobloch syndrome, one an isolated case and the other familial, Suzuki et al. (2002) could not detect any mutation in the COL18A1 gene, indicating nonallelic genetic heterogeneity of the disorder.

Analysis of 2 unrelated families with Knobloch syndrome from Hungary and New Zealand allowed Menzel et al. (2004) to confirm the involvement of COL18A1 in the pathogenesis of the disorder and to demonstrate the existence of genetic heterogeneity. Affected members of the Hungarian family were compound heterozygous for 2 mutations of the COL18A1 gene: a 1-bp insertion causing a frameshift and a premature in-frame stop codon (120328.0003) and an amino acid substitution (D104N endostatin/D1437N COL18A1; 120328.0004). The missense variant was located in a conserved amino acid of endostatin and was presumed to be pathogenic because Menzel et al. (2004) showed that the endostatin mutant was impaired in its affinity towards laminin; however, the authors considered that the D104N variant may also be in cis with an unidentified mutation. Iughetti et al. (2001) described this polymorphic change at residue 104 of endostatin. Suzuki et al. (2005) and Antonarakis et al. (2005) discussed the pathogenic role of this mutation in KNO1.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In a family (M175) that was the product of a first-cousin union with 5 healthy children and 2 affected with Knobloch syndrome, they identified a causative homozygous frameshift mutation in the COL18A1 gene (120328.0007).

By whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing of 4 patients from distinct consanguineous Turkish families with structural brain malformations and some characteristic features of Knobloch syndrome, Caglayan et al. (2014) identified 3 different homozygous frameshift mutations in the COL18A1 gene, 1 of which had previously been reported. All 3 mutations were located in either the alpha-helix or the endostatin domain.

Primary Closed-Angle Glaucoma

In affected members of a consanguineous 5-generation Iranian family segregating autosomal dominant primary angle-closure glaucoma mapping to chromosome 21q22 (GLCC; 618880), Suri et al. (2018) identified heterozygosity for a missense mutation in the COL18A1 gene (E184K; 120328.0010) that segregated with disease and was not found in ethnically matched controls. In the probands from 2 unrelated Iranian families with Knobloch syndrome-1, the authors identified homozygosity for frameshift mutations in COL18A1 (120328.0011 and 120328.0012). Examination of 6 heterozygous mutation carriers in the 2 families showed early evidence of iridocorneal angle closure in 4 of them; the other 2 carriers were relatively young, and the authors noted that COL18A1-associated angle closure appears to be a late-onset phenotype. The authors also suggested that mild presentations of angle closure might be overlooked in such families, in the context of the more severe disease of the offspring with KNO1.


Animal Model

Marneros and Olsen (2003) found that abnormalities in the iris and ciliary body of Col18a1 -/- mice demonstrated the important role of collagen XVIII in the function of ocular basement membranes. The absence of collagen XVIII altered the properties of basement membranes and led to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome (600510). In addition, loss of collagen XVIII created changes that allowed clump cells to migrate out of the iris. Marneros and Olsen (2003) showed that clump cells are macrophage-like cells which were able to penetrate the inner limiting membrane in mutant mice. They concluded that Col18a1 deficient mice might serve as a model of, and had demonstrated the potential importance of alterations in extracellular matrix components in, human pigment dispersion syndrome.

Utriainen et al. (2004) showed that Col18a1-null C57BL mice exhibited dilation of the brain ventricles with 20% of mice developing hydrocephalus. There was significant broadening of the epithelial basement membrane of the choroid plexuses (CP). The CP epithelial cell morphology was altered, and cells from Col18a1-null mice contained more vacuoles compared to cells from wildtype mice, suggestive of alterations in CSF production. Markedly broadened basement membranes were found in the atrioventricular valves of the heart and in the kidney tubules, whereas the glomerular mesangial matrix of kidneys was expanded in Col18a1-null mice and serum creatinine levels were elevated, indicating alterations in kidney filtration capacity. Utriainen et al. (2004) concluded that type XVIII collagen is a structurally important constituent of basement membranes and that its absence can result in a variety of phenotypic alterations.


ALLELIC VARIANTS ( 12 Selected Examples):

.0001 KNOBLOCH SYNDROME 1

COL18A1, IVS1AS, A-T, -2
  
RCV000018652...

Sertie et al. (2000) identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively in 12 Knobloch syndrome (KNO1; 267750) patients; the mutation was not found among 140 control chromosomes. Due to alternative splicing, the mutation creates a stop codon in exon 4, thus truncating the COL18A1 short form, which was otherwise expressed in human adult retina.


.0002 KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, 3514CT
  
RCV000055632...

Suzuki et al. (2002) reported genotyping studies of 3 unrelated patients with Knobloch syndrome (KNO1; 267750) who were compound heterozygotes for a 2-bp deletion (3514_3515delCT) in exon 41 of the COL18A1 gene, each in combination with a different mutant companion allele. The 2-bp deletion was on the paternal allele in 2 cases and on the maternal allele in the third. A different haplotype was associated with this common pathogenic allele, suggesting that the mutation had originated more than once. Two of these patients had an encephalocele that had been resected; the third had a bone defect visualized by CT scan. All 3 had myopia and vitreoretinal degeneration and 2 had had retinal detachment. One of the patients, aged 21 years, had been blind from the age of 5.

Paisan-Ruiz et al. (2009) reported 2 sisters from a small village in northern India who were homozygous for the 3514_3515delCT mutation. They had a complex neurologic disorder, including cognitive decline beginning around age 3 years, seizures, and adult-onset of progressive visual problems and cerebellar ataxia. The 48-year-old proband had glaucoma, lens dislocation, and retinal and corneal dystrophy. Cerebellar ataxia affected both upper and lower limbs, and she had nystagmus. She was independent for toileting and dressing. Brain MRI showed frontal polymicrogyria with severe cerebral and cerebellar atrophy. Her sister had a similar disease course. The 2-bp deletion occurred at nucleotide 3514 in isoform 2 and at nucleotide 4054 in isoform 1, resulting in frameshifts of both isoforms. Paisan-Ruiz et al. (2009) noted the expanding phenotypic variability associated with this mutation and with Knobloch syndrome.

Mahajan et al. (2010) reported 2 sisters, born of unrelated El Salvadorian parents, with Knobloch syndrome who were homozygous for the 3514delCT deletion. In addition to the occipital defect and classic ophthalmologic findings in both girls, 1 developed acute lymphoblastic leukemia (ALL), pre-B type, at age 4 years. Mahajan et al. (2010) speculated that lack of endostatin in these patients, resulting from the deletion, may have contributed to the development of ALL in 1 of the girls.


.0003 KNOBLOCH SYNDROME 1

COL18A1, 1-BP INS, 3363C
  
RCV000018654...

In a Hungarian family with Knobloch syndrome (KNO1; 267750), originally described by Czeizel et al. (1992), Menzel et al. (2004) found that affected members had compound heterozygosity for 2 mutations in the COL18A1 gene: a 1-bp insertion of a C in exon 35 (c.3363_3364insC) that created a frameshift and a premature stop codon in exon 40, and an asp1437-to-asn in the COL18A1 gene (D104N endostatin/D1437N COL18A1; 120328.0004). The variant was located at residue 104 in endostatin. Menzel et al. (2004) showed that endostatin N104 was impaired in its affinity towards laminin. A brother and sister had severe myopia, lens abnormalities, vitreal opacities, pigmented macular abnormalities, and retinal detachment. They each had an occipital meningocele at birth that was surgically removed and did not cause any subsequent problems. There was no cognitive impairment and a CT scan did not show any alterations in the cerebral ventricles and brain structure.


.0004 KNOBLOCH SYNDROME 1

COL18A1, ASP1437ASN
  
RCV000018655...

For discussion of the asp1437-to-asn (D1437N) mutation in the COL18A1 gene that was found in compound heterozygous state in patients with Knobloch syndrome (KNO1; 267750) by Menzel et al. (2004), see 120328.0003.


.0005 KNOBLOCH SYNDROME 1

COL18A1, IVS36DS, A-C, +3
  
RCV000018656

In 2 sibs with Knobloch syndrome (KNO1; 267750), born of consanguineous Algerian parents, Keren et al. (2007) identified a homozygous A-to-C transversion in intron 36 of the COL18A1 gene. The older sib had occipital meningocele, rapidly progressive myopia with subsequent retinal detachment at age 5 years, and evidence of a neuronal migration disorder with pachygyria and polymicrogyria. She showed mildly delayed development and learning disability.


.0006 KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, 3617CT
   RCV000022500

In affected members of a consanguineous Pakistani family with Knobloch syndrome (KNO1; 267750), originally reported by Khaliq et al. (2007), Joyce et al. (2010) identified a homozygous 2-bp deletion (3617delCT) in exon 40 of the COL18A1 gene, predicted to result in premature termination. The mutation was not found in 426 controls. The patients had myopia, vitreoretinal degeneration, and occipital scalp defect, but did not have encephalocele, retinal detachment, or cardiovascular abnormalities. This family had previously been reported to define a novel locus on chromosome 17q11.2 (KNO3), but the molecular results of Joyce et al. (2010) indicated that there is no evidence to support the KNO3 locus. The original mapping by Khaliq et al. (2007) used microsatellite markers, whereas the mapping by Joyce et al. (2010) used high-density SNP arrays.


.0007 KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL
  
RCV000022501

In a family (M175) in which first-cousin parents had 5 healthy children and 2 children with Knobloch syndrome (KNO1; 267750), characterized by intellectual disability and retinopathy, Najmabadi et al. (2011) identified a 2-bp deletion at genomic coordinate Chr21:45,754,433-45,754,434 (NCBI36) in the COL18A1 gene, resulting in a frameshift at codon 1587 (Leu1587fs). The mutation was found in homozygosity in affected individuals of the family.


.0008 KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, NT3514
   RCV000055632...

In the probands of 2 Saudi families with Knobloch syndrome (KNO1; 267750), Aldahmesh et al. (2013) identified a homozygous 1-bp deletion (c.3514_3515del) in the COL18A1 gene, resulting in a frameshift and premature termination (Leu1172ValfsTer72). One proband was 6 months old and had retinal detachment, high myopia, and occipital cutis aplasia. The other proband was an 11-year-old boy with various ocular anomalies, high myopia, and epilepsy. An Irish girl with the disorder was compound heterozygous for c.3514_3515del and a 1-bp duplication in the COL18A1 gene (c.2118dup), resulting in a frameshift and premature termination (Gly707ArgfsTer23; 120328.0009). She had high myopia, vitreous abnormalities, and a bald patch over the vertex of her head.


.0009 KNOBLOCH SYNDROME 1

COL18A1, 1-BP DUP, NT2118
  
RCV000055633...

For discussion of the 1-bp duplication in the COL18A1 gene (c.2118dup) that was found in compound heterozygous state in a patient with Knobloch syndrome (KNO1; 267750) by Aldahmesh et al. (2013), see 120328.0008.


.0010 GLAUCOMA, PRIMARY CLOSED ANGLE

COL18A1, GLU184LYS
  
RCV001093601...

In 10 affected members of a consanguineous 5-generation Iranian family (ANG200) segregating autosomal dominant primary angle-closure glaucoma (GLCC; 618880) mapping to chromosome 21q22, Suri et al. (2018) identified heterozygosity for a c.550G-A transition (c.550G-A, NM_130444.2) in the COL18A1 gene, resulting in a glu184-to-lys (E184K) substitution at a conserved residue within a noncollagenous domain between the coiled-coil motif and the frizzled-like domain. The authors also identified 1 family member (IV-7) who was homozygous for the E184K variant, a 53-year-old woman who showed only early evidence of iridocorneal angle closure. The mutation was not found in 400 ethnically matched healthy elderly controls.


.0011 KNOBLOCH SYNDROME 1

GLAUCOMA, PRIMARY CLOSED ANGLE, INCLUDED
COL18A1, 1-BP DEL, 1513C
  
RCV001093602...

In a 3-year-old boy from a consanguineous Iranian family (KS100) with Knobloch syndrome (KNO1; 267750), Suri et al. (2018) identified homozygosity for a 1-bp deletion (c.1513delC, NM_130444.2), causing a frameshift predicted to result in a premature termination codon (Arg505ValfsTer34). His father and his maternal and paternal grandmothers were heterozygous for the mutation, and all 3 carriers showed early evidence of primary angle-closure glaucoma (GLCC; 618880).


.0012 KNOBLOCH SYNDROME 1

GLAUCOMA, PRIMARY CLOSED ANGLE, INCLUDED
COL18A1, 1-BP DEL, 1834C
  
RCV001093604...

In a 12-year-old girl from a consanguineous Iranian family (KS101) with Knobloch syndrome (KNO1; 267750), Suri et al. (2018) identified homozygosity for a 1-bp deletion (c.1834delC, NM_130444.2), causing a frameshift predicted to result in a premature termination codon (Leu612TrpfsTer23). Her parents and paternal grandfather were heterozygous for the mutation; examination revealed that her 65-year-old grandfather showed early evidence of primary angle-closure glaucoma (GLCC; 618880), whereas her parents, who were 22 and 30 years younger, did not yet manifest the condition.


REFERENCES

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  18. Paisan-Ruiz, C., Scopes, G., Lee, P., Houlden, H. Homozygosity mapping through whole genome analysis identifies a COL18A1 mutation in an Indian family presenting with an autosomal recessive neurological disorder. Am. J. Med. Genet. 150B: 993-997, 2009. [PubMed: 19160445, related citations] [Full Text]

  19. Rehn, M., Hintikka, E., Pihlajaniemi, T. Characterization of the mouse gene for the alpha-1 chain of type XVIII collagen (Col18a1) reveals that the three variant N-terminal polypeptide forms are transcribed from two widely separated promoters. Genomics 32: 436-446, 1996. [PubMed: 8838808, related citations] [Full Text]

  20. Rehn, M., Pihlajaniemi, T. Alpha-1(XVIII), a collagen chain with frequent interruptions in the collagenous sequence, a distinct tissue distribution, and homology with type XV collagen. Proc. Nat. Acad. Sci. 91: 4234-4238, 1994. [PubMed: 8183894, related citations] [Full Text]

  21. Saarela, J., Ylikarppa, R., Rehn, M., Purmonen, S., Pihlajaniemi, T. Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biol. 16: 319-328, 1998. [PubMed: 9503365, related citations] [Full Text]

  22. Sertie, A. L., Sossi, V., Camargo, A. A., Zatz, M., Brahe, C., Passos-Bueno, M. R. Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum. Molec. Genet. 9: 2051-2058, 2000. [PubMed: 10942434, related citations] [Full Text]

  23. Shi, H., Huang, Y., Zhou, H., Song, X., Yuan, S., Fu, Y., Luo, Y. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. Blood 110: 2899-2906, 2007. [PubMed: 17615292, related citations] [Full Text]

  24. Sudhakar, A., Sugimoto, H., Yang, C., Lively, J., Zeisberg, M., Kalluri, R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha-V-beta-3 and alpha-5-beta-1 integrins. Proc. Nat. Acad. Sci. 100: 4766-4771, 2003. [PubMed: 12682293, images, related citations] [Full Text]

  25. Suri, F., Yazdani, S., Chapi, M., Safari, I., Rasooli, P., Daftarian, N., Jafarinasab, M. R., Firouzabadi, S. G., Alehabib, E., Darvish, H., Klotzle, B., Fan, J.-B., Turk, C., Elahi, E. COL18A1 is a candidate eye iridocorneal angle-closure gene in humans. Hum. Molec. Genet. 27: 3772-3786, 2018. [PubMed: 30007336, related citations] [Full Text]

  26. Suzuki, O. T., Bagatini, K., Sertie, A. L., Passos-Bueno, M. R. How pathogenic is the p.D104N/endostatin polymorphic allele of COL18A1 in Knobloch syndrome? (Letter) Hum. Mutat. 25: 314-315, 2005. [PubMed: 15714516, related citations] [Full Text]

  27. Suzuki, O. T., Sertie, A. L., Der Kaloustian, V. M., Kok, F., Carpenter, M., Murray, J., Czeizel, A. E., Kliemann, S. E., Rosemberg, S., Monteiro, M., Olsen, B. R., Passos-Bueno, M. R. Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. Am. J. Hum. Genet. 71: 1320-1329, 2002. [PubMed: 12415512, images, related citations] [Full Text]

  28. Utriainen, A., Sormunen, R., Kettunen, M., Carvalhaes, L. S., Sajanti, E., Eklund, L., Kauppinen, R., Kitten, G. T., Pihlajaniemi, T. Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Hum. Molec. Genet. 13: 2089-2099, 2004. [PubMed: 15254016, related citations] [Full Text]


Marla J. F. O'Neill - updated : 05/11/2020
Sonja A. Rasmussen - updated : 07/12/2019
Cassandra L. Kniffin - updated : 9/19/2013
Cassandra L. Kniffin - updated : 3/22/2012
Ada Hamosh - updated : 1/6/2012
Cassandra L. Kniffin - updated : 9/12/2011
Cassandra L. Kniffin - updated : 1/21/2010
Cassandra L. Kniffin - updated : 9/8/2008
Patricia A. Hartz - updated : 6/3/2008
Cassandra L. Kniffin - updated : 4/28/2008
George E. Tiller - updated : 3/21/2007
Victor A. McKusick - updated : 4/1/2005
Victor A. McKusick - updated : 2/3/2004
Jane Kelly - updated : 10/30/2003
Victor A. McKusick - updated : 1/8/2003
Victor A. McKusick - updated : 1/8/2003
Stylianos E. Antonarakis - updated : 8/6/2001
George E. Tiller - updated : 10/27/2000
Victor A. McKusick - updated : 5/12/1998
Victor A. McKusick - updated : 6/19/1997
Alan F. Scott - updated : 4/12/1996
Creation Date:
Victor A. McKusick : 12/20/1993
alopez : 02/28/2022
carol : 08/02/2021
alopez : 08/04/2020
carol : 05/11/2020
carol : 07/12/2019
carol : 12/30/2015
carol : 5/21/2015
mcolton : 5/20/2015
carol : 12/27/2013
carol : 9/20/2013
ckniffin : 9/19/2013
carol : 9/18/2013
alopez : 4/2/2012
ckniffin : 3/22/2012
carol : 1/6/2012
terry : 1/6/2012
carol : 9/12/2011
carol : 9/12/2011
ckniffin : 9/12/2011
wwang : 1/27/2010
ckniffin : 1/21/2010
carol : 3/12/2009
wwang : 9/12/2008
ckniffin : 9/8/2008
mgross : 6/12/2008
terry : 6/3/2008
wwang : 4/28/2008
wwang : 3/23/2007
terry : 3/21/2007
terry : 7/12/2005
alopez : 4/22/2005
wwang : 4/7/2005
wwang : 4/5/2005
terry : 4/1/2005
cwells : 2/9/2004
terry : 2/3/2004
tkritzer : 11/6/2003
tkritzer : 10/30/2003
tkritzer : 10/30/2003
tkritzer : 6/19/2003
tkritzer : 6/17/2003
cwells : 1/14/2003
terry : 1/8/2003
terry : 1/8/2003
mgross : 8/6/2001
mgross : 8/6/2001
carol : 12/7/2000
terry : 11/10/2000
mcapotos : 10/27/2000
carol : 6/28/2000
carol : 5/22/1998
carol : 5/21/1998
terry : 5/12/1998
jenny : 6/27/1997
jenny : 6/23/1997
mark : 6/19/1997
mark : 4/12/1996
terry : 4/12/1996
terry : 4/11/1996
mark : 4/10/1996
jason : 7/13/1994
mimadm : 4/14/1994
carol : 3/14/1994
carol : 12/20/1993

* 120328

COLLAGEN, TYPE XVIII, ALPHA-1; COL18A1


Other entities represented in this entry:

ENDOSTATIN, INCLUDED

HGNC Approved Gene Symbol: COL18A1

Cytogenetic location: 21q22.3     Genomic coordinates (GRCh38): 21:45,405,165-45,513,720 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.3 Glaucoma, primary closed-angle 618880 Autosomal dominant 3
Knobloch syndrome, type 1 267750 Autosomal recessive 3

TEXT

Cloning and Expression

Oh et al. (1994) isolated overlapping mouse cDNAs encoding a novel collagenous polypeptide, alpha-1(XVIII) collagen. Nucleotide sequence analysis showed that the COL18A1 gene contains 10 triple-helical domains separated and flanked by nontriple-helical regions. Within the nontriple-helical regions, there are several ser-gly-containing sequences that conform to the consensus sequences for glycosaminoglycan attachment sites in proteoglycan core proteins. Northern blot analysis detected COL18A1 transcripts in multiple organs, with the highest levels in liver, lung, and kidney.

Oh et al. (1994) reported the isolation of human cDNAs and genomic DNAs representing the COL18A1 gene.

Several lines of direct evidence show that angiogenesis is essential for the growth and persistence of solid tumors and metastases. To stimulate angiogenesis, tumors upregulate a variety of angiogenic factors. Many malignant tumors, however, also generate inhibitors of angiogenesis, including angiostatin. O'Reilly et al. (1994) discovered an angiogenesis inhibitor, designated angiostatin, that specifically inhibits endothelial cell proliferation. They showed that angiostatin is an internal fragment of plasminogen, containing at least 3 of the kringles of plasminogen. Using a rationale similar to that for the isolation of angiostatin, O'Reilly et al. (1997) isolated a 20-kD angiogenesis inhibitor, which they called endostatin, from a murine hemangioendothelioma. They found that endostatin is a C-terminal fragment of collagen XVIII. Systemic therapy with endostatin caused the nearly complete suppression of tumor-induced angiogenesis and strong antitumor activity.

Saarela et al. (1998) reported full-length human type XVIII collagen cDNAs that encode 2 variant chains of 1,516 and 1,336 residues. They found that the 2 chains have different signal peptides and N-terminal NC1 domains. The amino acid sequences of the human and previously characterized mouse alpha-1(XVIII) chains exhibited an overall identity of 79%. The highest homology between these chains was observed in their last 184 residues, corresponding to the proteolytic fragment endostatin.

Using immunohistochemical and expression analyses, Caglayan et al. (2014) identified COL18A1 expression in the pia and blood vessels of the developing human cerebral cortex, supporting a role for COL18A1 in human neurodevelopment.


Gene Structure

Rehn et al. (1996) showed that the mouse Col18a1 gene contains 43 exons spanning over 100 kb and that 2 alternative promoters are used. Promoter 1, which is about 50 kb upstream and adjacent to exons 1 and 2, produces a transcript that skips exon 3. Promoter 2, adjacent to exon 3, produces 2 types of transcripts depending on alternative splicing of that exon. All 3 predicted proteins differ in their amino-terminal noncollagenous domains.


Mapping

Using a genomic clone as a probe for fluorescence in situ hybridization, Oh et al. (1994) mapped the COL18A1 gene to 21q22.3. In addition, using an interspecific backcross panel, they showed that the murine Col18a1 is on chromosome 10, close to the Col6a1 and Col6a2 genes.


Gene Function

Upon comparison of COL18A1 sequences with those of COL15A1 (120325), Oh et al. (1994) observed a striking similarity in the lengths of the 6 most carboxyl-terminal triple-helical domains. In addition, within the carboxyl nontriple-helical domain NC1 of the 2 chains, a region of 177 amino acid residues showed about 60% identity. The similarities in structure suggested that the collagens are functionally related, and their distinct structure pointed to differences from other known collagen types. Oh et al. (1994) concluded that they belonged to a novel subfamily of extracellular matrix proteins with multiple triple-helical domains, and proposed to designate these as multiplexins, for 'protein with multiple triple-helix domains and interruptions.'

Based on mouse cDNA clones, Rehn and Pihlajaniemi (1994) likewise pointed out the homology between type XVIII and type XV collagens. Northern blot analysis demonstrated a striking tissue distribution for type XVIII collagen mRNAs, as the clones hybridized strongly with mRNAs of 4.3 and 5.3 kilobases that were present only in lung and liver of the 8 mouse tissues studied.

Endostatin is a potent antiangiogenic protein. Karumanchi et al. (2001) showed that alkaline phosphatase-tagged endostatin bound endothelial cells, revealing 2 binding affinities. Expression cloning identified the cell surface proteoglycan glypican, specifically glypican-1 (600395) or glypican-4 (300168), as the lower-affinity receptor. Biochemical and genetic studies indicated that the heparan sulfate glycosaminoglycans of glypican were critical for endostatin binding. Furthermore, endostatin selected a specific octasulfated hexasaccharide from a sequence in heparin. Karumanchi et al. (2001) also demonstrated a role for endostatin in renal tubular cell branching morphogenesis and showed that glypicans serve as low-affinity receptors for endostatin in these cells, as in endothelial cells. Antisense experiments suggested the critical importance of glypicans in mediating endostatin activities.

In humans, the COL18A1 gene encodes 2 distinct isoforms by use of 2 promoters, 1 of which is located upstream from exon 1 and the other of which is located upstream from exon 3 (Saarela et al., 1998). The 2 isoforms differ only at their signal peptides, with different N-terminal noncollagenous domains that are 303 or 493 residues in length.

Suzuki et al. (2002) showed that the longer human COL18A1 isoform, with 728 residues, is expressed in several tissues including the human eye. Lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but those patients who lack all forms present more severe ocular alterations.

Tumstatin and endostatin, 2 inhibitors of angiogenesis, derive from the precursor human collagen molecules COL4A3 (120070) and COL18A1, respectively. Although both of these inhibitors are NC1 domain fragments of collagens, they share only 14% amino acid homology. Sudhakar et al. (2003) evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these 2 collagen-derived inhibitors. Tumstatin prevents angiogenesis through inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas endostatin prevents endothelial cell migration with no effect on proliferation. Sudhakar et al. (2003) demonstrated that tumstatin binds to alpha-V-beta-3 integrin (193210, 173470) in a vitronectin/fibronectin/RGD cyclic peptide-independent manner, whereas endostatin competes with fibronectin/RGD cyclic peptide to bind alpha-5-beta-1 integrin (135620, 135630). The activity of tumstatin is mediated by alpha-V-beta-3 integrin, whereas the activity of endostatin is mediated by alpha-5-beta-1 integrin. Because of the distinct properties of tumstatin and endostatin, indicating their diverse antiangiogenic actions, the authors suggested the 2 be combined for targeting tumor angiogenesis.

By immunoprecipitation analysis using membrane fractions of human mammary epithelial cells, Shi et al. (2007) showed that endostatin specifically bound to cell surface nucleolin (NCL; 164035) with high affinity. Blockage of nucleolin with neutralizing antibody or knockdown of nucleolin by RNA interference countered the antiendothelial activity of endostatin and abrogated its antiangiogenic and antitumor activity in vivo. Nucleolin and endostatin colocalized on the cell surface of endothelial cells in tumors, and endostatin was internalized and transported into cell nuclei of endothelial cells via nucleolin. In the nucleus, phosphorylation of nucleolin, which is critical for cell proliferation, was inhibited by endostatin. Shi et al. (2007) concluded that nucleolin is an endostatin receptor that mediates the antiangiogenic and antitumor activities of endostatin.


Molecular Genetics

Knobloch Syndrome 1

Knobloch syndrome-1 (KNO1; 267750) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities, and occipital encephalocele. The KNO1 causative gene had been assigned to a 4.3-cM interval at 21q22.3 by linkage analysis in a large consanguineous Brazilian family. Sertie et al. (2000) narrowed the candidate interval to a region of less than 245 kb, which contained 24 expressed sequence tags, including the 5-prime end of the COL18A1 gene. They identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 (120328.0001) in 12 patients with Knobloch syndrome. Due to alternative splicing, the mutation creates a stop codon in exon 4, thus truncating the alpha-1(XVIII) collagen short form, which was otherwise expressed in human adult retina. The authors concluded that Knobloch syndrome-1 is caused by mutations in the COL18A1 gene, which may play a major role in retinal structure as well as in the closure of the neural tube.

Suzuki et al. (2002) screened the entire coding region and the exon-intron boundaries of the COL18A1 gene in 8 unrelated patients with Knobloch syndrome. Sixty different pathogenic changes were identified in alleles of 5 unrelated patients with KNO1 (3 compound heterozygotes and 2 homozygotes). All were truncating mutations leading to deficiency of 1 or all collagen XVIII isoforms and endostatin. A 2-bp mutation in exon 41 (120328.0002) was found in 3 unrelated individuals, each on a different haplotype, suggesting that this mutation had occurred more than once. Suzuki et al. (2002) found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms. None of the patients with mutations in the COL18A1 gene had any major kidney or liver defects, which was surprising because the 3 isoforms are highly expressed in these organs. The lack of collagen XVIII may be compensated by collagen XV (120325). Suzuki et al. (2002) suggested that predisposition to epilepsy might be due to abnormal neuronal migration. In 2 patients with Knobloch syndrome, one an isolated case and the other familial, Suzuki et al. (2002) could not detect any mutation in the COL18A1 gene, indicating nonallelic genetic heterogeneity of the disorder.

Analysis of 2 unrelated families with Knobloch syndrome from Hungary and New Zealand allowed Menzel et al. (2004) to confirm the involvement of COL18A1 in the pathogenesis of the disorder and to demonstrate the existence of genetic heterogeneity. Affected members of the Hungarian family were compound heterozygous for 2 mutations of the COL18A1 gene: a 1-bp insertion causing a frameshift and a premature in-frame stop codon (120328.0003) and an amino acid substitution (D104N endostatin/D1437N COL18A1; 120328.0004). The missense variant was located in a conserved amino acid of endostatin and was presumed to be pathogenic because Menzel et al. (2004) showed that the endostatin mutant was impaired in its affinity towards laminin; however, the authors considered that the D104N variant may also be in cis with an unidentified mutation. Iughetti et al. (2001) described this polymorphic change at residue 104 of endostatin. Suzuki et al. (2005) and Antonarakis et al. (2005) discussed the pathogenic role of this mutation in KNO1.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In a family (M175) that was the product of a first-cousin union with 5 healthy children and 2 affected with Knobloch syndrome, they identified a causative homozygous frameshift mutation in the COL18A1 gene (120328.0007).

By whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing of 4 patients from distinct consanguineous Turkish families with structural brain malformations and some characteristic features of Knobloch syndrome, Caglayan et al. (2014) identified 3 different homozygous frameshift mutations in the COL18A1 gene, 1 of which had previously been reported. All 3 mutations were located in either the alpha-helix or the endostatin domain.

Primary Closed-Angle Glaucoma

In affected members of a consanguineous 5-generation Iranian family segregating autosomal dominant primary angle-closure glaucoma mapping to chromosome 21q22 (GLCC; 618880), Suri et al. (2018) identified heterozygosity for a missense mutation in the COL18A1 gene (E184K; 120328.0010) that segregated with disease and was not found in ethnically matched controls. In the probands from 2 unrelated Iranian families with Knobloch syndrome-1, the authors identified homozygosity for frameshift mutations in COL18A1 (120328.0011 and 120328.0012). Examination of 6 heterozygous mutation carriers in the 2 families showed early evidence of iridocorneal angle closure in 4 of them; the other 2 carriers were relatively young, and the authors noted that COL18A1-associated angle closure appears to be a late-onset phenotype. The authors also suggested that mild presentations of angle closure might be overlooked in such families, in the context of the more severe disease of the offspring with KNO1.


Animal Model

Marneros and Olsen (2003) found that abnormalities in the iris and ciliary body of Col18a1 -/- mice demonstrated the important role of collagen XVIII in the function of ocular basement membranes. The absence of collagen XVIII altered the properties of basement membranes and led to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome (600510). In addition, loss of collagen XVIII created changes that allowed clump cells to migrate out of the iris. Marneros and Olsen (2003) showed that clump cells are macrophage-like cells which were able to penetrate the inner limiting membrane in mutant mice. They concluded that Col18a1 deficient mice might serve as a model of, and had demonstrated the potential importance of alterations in extracellular matrix components in, human pigment dispersion syndrome.

Utriainen et al. (2004) showed that Col18a1-null C57BL mice exhibited dilation of the brain ventricles with 20% of mice developing hydrocephalus. There was significant broadening of the epithelial basement membrane of the choroid plexuses (CP). The CP epithelial cell morphology was altered, and cells from Col18a1-null mice contained more vacuoles compared to cells from wildtype mice, suggestive of alterations in CSF production. Markedly broadened basement membranes were found in the atrioventricular valves of the heart and in the kidney tubules, whereas the glomerular mesangial matrix of kidneys was expanded in Col18a1-null mice and serum creatinine levels were elevated, indicating alterations in kidney filtration capacity. Utriainen et al. (2004) concluded that type XVIII collagen is a structurally important constituent of basement membranes and that its absence can result in a variety of phenotypic alterations.


ALLELIC VARIANTS 12 Selected Examples):

.0001   KNOBLOCH SYNDROME 1

COL18A1, IVS1AS, A-T, -2
SNP: rs1467976097, gnomAD: rs1467976097, ClinVar: RCV000018652, RCV001851919

Sertie et al. (2000) identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively in 12 Knobloch syndrome (KNO1; 267750) patients; the mutation was not found among 140 control chromosomes. Due to alternative splicing, the mutation creates a stop codon in exon 4, thus truncating the COL18A1 short form, which was otherwise expressed in human adult retina.


.0002   KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, 3514CT
SNP: rs398122391, gnomAD: rs398122391, ClinVar: RCV000055632, RCV000479282, RCV000504900, RCV000505165, RCV001074487, RCV001198207, RCV002504954, RCV003235024

Suzuki et al. (2002) reported genotyping studies of 3 unrelated patients with Knobloch syndrome (KNO1; 267750) who were compound heterozygotes for a 2-bp deletion (3514_3515delCT) in exon 41 of the COL18A1 gene, each in combination with a different mutant companion allele. The 2-bp deletion was on the paternal allele in 2 cases and on the maternal allele in the third. A different haplotype was associated with this common pathogenic allele, suggesting that the mutation had originated more than once. Two of these patients had an encephalocele that had been resected; the third had a bone defect visualized by CT scan. All 3 had myopia and vitreoretinal degeneration and 2 had had retinal detachment. One of the patients, aged 21 years, had been blind from the age of 5.

Paisan-Ruiz et al. (2009) reported 2 sisters from a small village in northern India who were homozygous for the 3514_3515delCT mutation. They had a complex neurologic disorder, including cognitive decline beginning around age 3 years, seizures, and adult-onset of progressive visual problems and cerebellar ataxia. The 48-year-old proband had glaucoma, lens dislocation, and retinal and corneal dystrophy. Cerebellar ataxia affected both upper and lower limbs, and she had nystagmus. She was independent for toileting and dressing. Brain MRI showed frontal polymicrogyria with severe cerebral and cerebellar atrophy. Her sister had a similar disease course. The 2-bp deletion occurred at nucleotide 3514 in isoform 2 and at nucleotide 4054 in isoform 1, resulting in frameshifts of both isoforms. Paisan-Ruiz et al. (2009) noted the expanding phenotypic variability associated with this mutation and with Knobloch syndrome.

Mahajan et al. (2010) reported 2 sisters, born of unrelated El Salvadorian parents, with Knobloch syndrome who were homozygous for the 3514delCT deletion. In addition to the occipital defect and classic ophthalmologic findings in both girls, 1 developed acute lymphoblastic leukemia (ALL), pre-B type, at age 4 years. Mahajan et al. (2010) speculated that lack of endostatin in these patients, resulting from the deletion, may have contributed to the development of ALL in 1 of the girls.


.0003   KNOBLOCH SYNDROME 1

COL18A1, 1-BP INS, 3363C
SNP: rs769882681, gnomAD: rs769882681, ClinVar: RCV000018654, RCV001588817

In a Hungarian family with Knobloch syndrome (KNO1; 267750), originally described by Czeizel et al. (1992), Menzel et al. (2004) found that affected members had compound heterozygosity for 2 mutations in the COL18A1 gene: a 1-bp insertion of a C in exon 35 (c.3363_3364insC) that created a frameshift and a premature stop codon in exon 40, and an asp1437-to-asn in the COL18A1 gene (D104N endostatin/D1437N COL18A1; 120328.0004). The variant was located at residue 104 in endostatin. Menzel et al. (2004) showed that endostatin N104 was impaired in its affinity towards laminin. A brother and sister had severe myopia, lens abnormalities, vitreal opacities, pigmented macular abnormalities, and retinal detachment. They each had an occipital meningocele at birth that was surgically removed and did not cause any subsequent problems. There was no cognitive impairment and a CT scan did not show any alterations in the cerebral ventricles and brain structure.


.0004   KNOBLOCH SYNDROME 1

COL18A1, ASP1437ASN
SNP: rs12483377, gnomAD: rs12483377, ClinVar: RCV000018655, RCV000248578, RCV000711309

For discussion of the asp1437-to-asn (D1437N) mutation in the COL18A1 gene that was found in compound heterozygous state in patients with Knobloch syndrome (KNO1; 267750) by Menzel et al. (2004), see 120328.0003.


.0005   KNOBLOCH SYNDROME 1

COL18A1, IVS36DS, A-C, +3
SNP: rs770631950, gnomAD: rs770631950, ClinVar: RCV000018656

In 2 sibs with Knobloch syndrome (KNO1; 267750), born of consanguineous Algerian parents, Keren et al. (2007) identified a homozygous A-to-C transversion in intron 36 of the COL18A1 gene. The older sib had occipital meningocele, rapidly progressive myopia with subsequent retinal detachment at age 5 years, and evidence of a neuronal migration disorder with pachygyria and polymicrogyria. She showed mildly delayed development and learning disability.


.0006   KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, 3617CT
ClinVar: RCV000022500

In affected members of a consanguineous Pakistani family with Knobloch syndrome (KNO1; 267750), originally reported by Khaliq et al. (2007), Joyce et al. (2010) identified a homozygous 2-bp deletion (3617delCT) in exon 40 of the COL18A1 gene, predicted to result in premature termination. The mutation was not found in 426 controls. The patients had myopia, vitreoretinal degeneration, and occipital scalp defect, but did not have encephalocele, retinal detachment, or cardiovascular abnormalities. This family had previously been reported to define a novel locus on chromosome 17q11.2 (KNO3), but the molecular results of Joyce et al. (2010) indicated that there is no evidence to support the KNO3 locus. The original mapping by Khaliq et al. (2007) used microsatellite markers, whereas the mapping by Joyce et al. (2010) used high-density SNP arrays.


.0007   KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL
SNP: rs398122391, gnomAD: rs398122391, ClinVar: RCV000022501

In a family (M175) in which first-cousin parents had 5 healthy children and 2 children with Knobloch syndrome (KNO1; 267750), characterized by intellectual disability and retinopathy, Najmabadi et al. (2011) identified a 2-bp deletion at genomic coordinate Chr21:45,754,433-45,754,434 (NCBI36) in the COL18A1 gene, resulting in a frameshift at codon 1587 (Leu1587fs). The mutation was found in homozygosity in affected individuals of the family.


.0008   KNOBLOCH SYNDROME 1

COL18A1, 2-BP DEL, NT3514
ClinVar: RCV000055632, RCV000479282, RCV000504900, RCV000505165, RCV001074487, RCV001198207, RCV002504954, RCV003235024

In the probands of 2 Saudi families with Knobloch syndrome (KNO1; 267750), Aldahmesh et al. (2013) identified a homozygous 1-bp deletion (c.3514_3515del) in the COL18A1 gene, resulting in a frameshift and premature termination (Leu1172ValfsTer72). One proband was 6 months old and had retinal detachment, high myopia, and occipital cutis aplasia. The other proband was an 11-year-old boy with various ocular anomalies, high myopia, and epilepsy. An Irish girl with the disorder was compound heterozygous for c.3514_3515del and a 1-bp duplication in the COL18A1 gene (c.2118dup), resulting in a frameshift and premature termination (Gly707ArgfsTer23; 120328.0009). She had high myopia, vitreous abnormalities, and a bald patch over the vertex of her head.


.0009   KNOBLOCH SYNDROME 1

COL18A1, 1-BP DUP, NT2118
SNP: rs775168204, gnomAD: rs775168204, ClinVar: RCV000055633, RCV001561888, RCV003335083

For discussion of the 1-bp duplication in the COL18A1 gene (c.2118dup) that was found in compound heterozygous state in a patient with Knobloch syndrome (KNO1; 267750) by Aldahmesh et al. (2013), see 120328.0008.


.0010   GLAUCOMA, PRIMARY CLOSED ANGLE

COL18A1, GLU184LYS
SNP: rs749957649, gnomAD: rs749957649, ClinVar: RCV001093601, RCV001856282

In 10 affected members of a consanguineous 5-generation Iranian family (ANG200) segregating autosomal dominant primary angle-closure glaucoma (GLCC; 618880) mapping to chromosome 21q22, Suri et al. (2018) identified heterozygosity for a c.550G-A transition (c.550G-A, NM_130444.2) in the COL18A1 gene, resulting in a glu184-to-lys (E184K) substitution at a conserved residue within a noncollagenous domain between the coiled-coil motif and the frizzled-like domain. The authors also identified 1 family member (IV-7) who was homozygous for the E184K variant, a 53-year-old woman who showed only early evidence of iridocorneal angle closure. The mutation was not found in 400 ethnically matched healthy elderly controls.


.0011   KNOBLOCH SYNDROME 1

GLAUCOMA, PRIMARY CLOSED ANGLE, INCLUDED
COL18A1, 1-BP DEL, 1513C
SNP: rs2035293928, ClinVar: RCV001093602, RCV001093603

In a 3-year-old boy from a consanguineous Iranian family (KS100) with Knobloch syndrome (KNO1; 267750), Suri et al. (2018) identified homozygosity for a 1-bp deletion (c.1513delC, NM_130444.2), causing a frameshift predicted to result in a premature termination codon (Arg505ValfsTer34). His father and his maternal and paternal grandmothers were heterozygous for the mutation, and all 3 carriers showed early evidence of primary angle-closure glaucoma (GLCC; 618880).


.0012   KNOBLOCH SYNDROME 1

GLAUCOMA, PRIMARY CLOSED ANGLE, INCLUDED
COL18A1, 1-BP DEL, 1834C
SNP: rs2035305918, ClinVar: RCV001093604, RCV001093605

In a 12-year-old girl from a consanguineous Iranian family (KS101) with Knobloch syndrome (KNO1; 267750), Suri et al. (2018) identified homozygosity for a 1-bp deletion (c.1834delC, NM_130444.2), causing a frameshift predicted to result in a premature termination codon (Leu612TrpfsTer23). Her parents and paternal grandfather were heterozygous for the mutation; examination revealed that her 65-year-old grandfather showed early evidence of primary angle-closure glaucoma (GLCC; 618880), whereas her parents, who were 22 and 30 years younger, did not yet manifest the condition.


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Contributors:
Marla J. F. O'Neill - updated : 05/11/2020
Sonja A. Rasmussen - updated : 07/12/2019
Cassandra L. Kniffin - updated : 9/19/2013
Cassandra L. Kniffin - updated : 3/22/2012
Ada Hamosh - updated : 1/6/2012
Cassandra L. Kniffin - updated : 9/12/2011
Cassandra L. Kniffin - updated : 1/21/2010
Cassandra L. Kniffin - updated : 9/8/2008
Patricia A. Hartz - updated : 6/3/2008
Cassandra L. Kniffin - updated : 4/28/2008
George E. Tiller - updated : 3/21/2007
Victor A. McKusick - updated : 4/1/2005
Victor A. McKusick - updated : 2/3/2004
Jane Kelly - updated : 10/30/2003
Victor A. McKusick - updated : 1/8/2003
Victor A. McKusick - updated : 1/8/2003
Stylianos E. Antonarakis - updated : 8/6/2001
George E. Tiller - updated : 10/27/2000
Victor A. McKusick - updated : 5/12/1998
Victor A. McKusick - updated : 6/19/1997
Alan F. Scott - updated : 4/12/1996

Creation Date:
Victor A. McKusick : 12/20/1993

Edit History:
alopez : 02/28/2022
carol : 08/02/2021
alopez : 08/04/2020
carol : 05/11/2020
carol : 07/12/2019
carol : 12/30/2015
carol : 5/21/2015
mcolton : 5/20/2015
carol : 12/27/2013
carol : 9/20/2013
ckniffin : 9/19/2013
carol : 9/18/2013
alopez : 4/2/2012
ckniffin : 3/22/2012
carol : 1/6/2012
terry : 1/6/2012
carol : 9/12/2011
carol : 9/12/2011
ckniffin : 9/12/2011
wwang : 1/27/2010
ckniffin : 1/21/2010
carol : 3/12/2009
wwang : 9/12/2008
ckniffin : 9/8/2008
mgross : 6/12/2008
terry : 6/3/2008
wwang : 4/28/2008
wwang : 3/23/2007
terry : 3/21/2007
terry : 7/12/2005
alopez : 4/22/2005
wwang : 4/7/2005
wwang : 4/5/2005
terry : 4/1/2005
cwells : 2/9/2004
terry : 2/3/2004
tkritzer : 11/6/2003
tkritzer : 10/30/2003
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tkritzer : 6/19/2003
tkritzer : 6/17/2003
cwells : 1/14/2003
terry : 1/8/2003
terry : 1/8/2003
mgross : 8/6/2001
mgross : 8/6/2001
carol : 12/7/2000
terry : 11/10/2000
mcapotos : 10/27/2000
carol : 6/28/2000
carol : 5/22/1998
carol : 5/21/1998
terry : 5/12/1998
jenny : 6/27/1997
jenny : 6/23/1997
mark : 6/19/1997
mark : 4/12/1996
terry : 4/12/1996
terry : 4/11/1996
mark : 4/10/1996
jason : 7/13/1994
mimadm : 4/14/1994
carol : 3/14/1994
carol : 12/20/1993