Molecular Analysis of Collagen XVIII Reveals Novel Mutations, Presence of a Third Isoform, and Possible Genetic Heterogeneity in Knobloch Syndrome

Abstract

Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.

Loss of Collagen XVIII Enhances Neovascularization and Vascular Permeability in Atherosclerosis

“…Interestingly, some Knobloch syndrome patients have Col18a1 mutations predicted to encode similar truncated proteins. 13,32 The young ages of these rare patients impede detection of increased atherosclerosis risk. Our data predict that carriers of Knobloch syndrome Col18a1 mutations could have increased susceptibility for atherosclerosis.…”

DNA sequence and comparative analysis of chimpanzee chromosome 22

“…For instance, IFNAR2, IFNGR2, CXADR, ITSN1 and CRYZL1 are directly or indirectly involved in the immune response against various pathogens. SH3BGR is strongly expressed in the developing heart, C21orf2 is expressed in the peripheral nervous system, SYNJ1 and ANKRD3 are signalling molecules acting in early brain development, MCM3AP is associated with cell cycle progression, ETS2 is a transcription factor essential for embryonic development and COL18A1 is a collagen gene that is mutated in human Knobloch syndrome associated with encephalocele 44 .…”

Transgenic isolation of skeletal muscle and kidney defects in lamininβ2 mutant mice: implications for Pierson syndrome

“…Perhaps the best evidence for this is the fact that mutations in genes encoding BM proteins cause human disease, despite substitution by related isoforms in some cases. For example, Alport syndrome is a type IV collagen disease of kidney and inner ear (Kashtan, 2004); Knobloch syndrome is a collagen XVIII (heparan sulfate proteoglycan) disease affecting the eye (Suzuki et al, 2002); and Herlitz's junctional epidermolysis bullosa and congenital muscular dystrophy type 1A are laminin diseases of the skin and neuromuscular system, respectively (Burgeson and Christiano, 1997;Patton, 2000).…”