Journal article
Molecular Analysis of Collagen XVIII Reveals Novel Mutations, Presence of a Third Isoform, and Possible Genetic Heterogeneity in Knobloch Syndrome
American journal of human genetics, Vol.71(6), pp.1320-1329
12/01/2002
DOI: 10.1086/344695
PMCID: PMC378571
PMID: 12415512
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.
Details
- Title: Subtitle
- Molecular Analysis of Collagen XVIII Reveals Novel Mutations, Presence of a Third Isoform, and Possible Genetic Heterogeneity in Knobloch Syndrome
- Creators
- O.T. Suzuki - Instituto BiológicoA.L. Sertié - Instituto BiológicoV.M. Der Kaloustian - McGill UniversityF. Kok - Departamento de Neurologia, Faculdade de Medicina, São Paulo, BrasilM. Carpenter - Maine Medical CenterJ. Murray - University of IowaA.E. Czeizel - Hereditary Disease FoundationS.E. Kliemann - Faculdade de Ciências Médicas da Santa Casa de São PauloS. Rosemberg - Faculdade de Ciências Médicas da Santa Casa de São PauloM. Monteiro - Departamento de Oftalmologia, Universidade de São Paulo, São Paulo, BrasilB.R. Olsen - Harvard UniversityM.R. Passos-Bueno - Instituto Biológico
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.71(6), pp.1320-1329
- DOI
- 10.1086/344695
- PMID
- 12415512
- PMCID
- PMC378571
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc
- Number of pages
- 10
- Language
- English
- Date published
- 12/01/2002
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985034985702771
Metrics
3 Record Views