title: Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin.
abstract: Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment, and congenital encephalocele. Pathogenic mutations in the COL18A1 gene on 21q22.3 were recently identified in KNO families. Analysis of two unrelated KNO families from Hungary and New Zealand allowed us to confirm the involvement of COL18A1 in the pathogenesis of KNO and to demonstrate the existence of genetic heterogeneity. Two COL18A1 mutations were identified in the Hungarian family: a 1-bp insertion causing a frameshift and a premature in-frame stop codon and an amino acid substitution. This missense variant is located in a conserved amino acid of endostatin, a cleavage product of the carboxy-terminal domain of collagen alpha 1 XVIII. D1437N (D104N in endostatin) likely represents a pathogenic mutation, as we show that the endostatin N104 mutant is impaired in its affinity towards laminin. Linkage to the COL18A1 locus was excluded in the New Zealand family, providing evidence for the existence of a second KNO locus. We named the second unmapped locus for Knobloch syndrome KNO2. Mutation analysis excluded COL15A1, a member of the multiplexin collagen subfamily similar to COL18A1, as being responsible for KNO2.
authors.affiliation: Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Menzel
authors.forename: Reidunn C J
authors.initials: RC
authors.lastname: Bekkeheien
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
authors.forename: Naomi
authors.initials: N
authors.lastname: Fukai
authors.forename: Eileen
authors.initials: E
authors.lastname: Boye
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Kosztolanyi
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
mesh_terms: D000595:Amino Acid Sequence; D002531:Cerebellum / Q000002:abnormalities; D043170:Collagen Type XVIII / Q000235:genetics*; D004677:Encephalocele / Q000235:genetics; D043169:Endostatins / Q000235:genetics*; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009216:Myopia / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D012162:Retinal Degeneration / Q000235:genetics; D012163:Retinal Detachment / Q000235:genetics; D016415:Sequence Alignment; D013577:Syndrome
chemical_list: D043170:Collagen Type XVIII; D043169:Endostatins