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

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...

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Bibliographic Details
Published in:	American journal of human genetics Vol. 71; no. 6; pp. 1320 - 1329
Main Authors:	Suzuki, O.T., Sertié, 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.
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-12-2002 University of Chicago Press The American Society of Human Genetics
Subjects:	Adolescent Adult Biological and medical sciences Child Child, Preschool Collagen - blood Collagen - genetics Collagen Type XVIII Complex syndromes Endostatins Exons - genetics Eye Abnormalities - genetics Female Genetic Heterogeneity Haplotypes - genetics Humans Infant Infant, Newborn Introns - genetics Male Medical genetics Medical sciences Molecular Sequence Data Mutation - genetics Pedigree Peptide Fragments - blood Peptide Fragments - genetics Phenotype Polymorphism, Genetic - genetics Protein Isoforms - genetics Retinal Degeneration - genetics Retinal Detachment - genetics RNA, Messenger - genetics RNA, Messenger - metabolism Syndrome Human Heterogeneity Knobloch syndrome Eye disease Pathogenesis Collagen Central nervous system disease Mutation Complex syndrome Congenital disease Genetic determinism Genetic disease
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0002-9297 1537-6605
DOI:	10.1086/344695