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)

Abstract

Knobloch syndrome (KS) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele. The KS causative gene had been assigned to a 4.3 cM interval at 21q22.3 by linkage analysis of a large consanguineous Brazilian family. We reconstructed the haplotypes of this family with ten additional markers (five were novel) and narrowed the candidate interval to a region of<245 kb, which contains 24 expressed sequence tags, the KIAA0958 gene and the 5' end of the COL18A1 gene. We identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively among the 12 KS patients, which was not found among 140 control chromosomes. This mutation predicts the creation of a stop codon in exon 4 and therefore the truncation of the alpha1(XVIII) collagen short form, which was expressed in human adult retina. These findings provide evidence that KS is caused by mutations in COL18A1 which, therefore, has a major role in determining the retinal structure as well as in the closure of the neural tube. Therefore, we show for the first time that the absence of a collagen isoform impairs embryonic cell proliferation and/or migration as a primary or secondary effect.

Characterization of drCol 15a1b: A Novel Component of the Stem Cell Niche in the Zebrafish Retina

“…This hypothesis is supported by the fact that collagen XVIII is a heparan-sulfate proteoglycan that is expressed in the chicken retina [54] as well as in the mammalian retina and fetal brain [24]. Furthermore, mutations in the col 18a1 gene in mammals are responsible for the Knobloch syndrome, an autosomal recessive disorder, which is characterized by myopia, vitreoretinal degeneration, and occipital encephalocele [22][23][24], and similar defects are found in the drCol 15a1b morphants. These findings represent further evidence of the complex evolution and functional divergence of gene families and of the conserved common regulatory functions that, in this case, might be involved in harnessing adult stem cell biology.…”

Evaluation and management of pediatric rhegmatogenous retinal detachment

“…Knobloch syndrome is associated with autosomal recessive mutations in the COL18A1 gene, which codes for type XVIII collagen. 41 The antiangiogenic protein, endostatin is also derived from type XVIII collagen. 37 A single family has also been reported with Knobloch syndrome and an autosomal recessive mutation in the ADAMTS18 gene, which encodes for a zinc metalloproteinase of unknown function that is expressed highly in the lens and retina.…”

Origin and turnover of ECM proteins from the inner limiting membrane and vitreous body

“…11,12 The enzymatic disruption of the ILM in chick embryos also led to an increase in eye size by 30%. 13 The fact that mutations of collagen XVIII, one of the three proteoglycans in the ILM, causes congenital high myopia 14 indicates that the ILM may also have a function in regulating eye size during embryogenesis. In the adult, the ILM is dispensable and its surgical removal is even considered beneficial for patients undergoing macular hole surgery.…”