title: High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1.
abstract: Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, skeletal, and auditory systems. To date three genes, COL2A1, COL11A1, and COL11A2, encoding the heterotypic type II/XI collagen fibrils present in vitreous and cartilage have been shown to have mutations that result in Stickler syndrome. As systemic features in this disorder are variable we have used an ophthalmic examination to differentiate those patients with a membranous vitreous phenotype associated with mutations in COL2A1, from other patients who may have mutations in other genes. Gene amplification and exon sequencing was used to screen 50 families or sporadic cases with this membranous phenotype, for mutations in COL2A1. Mutations were detected in 47 (94%) cases consisting of 166 affected and 78 unaffected individuals. We also demonstrate that the predominantly ocular form of type 1 Stickler syndrome is not confined to mutations in the alternatively spliced exon 2. Using splicing reporter constructs we demonstrate that a mutant GC donor splice site in intron 51 can be spliced normally; this contributed to the predominantly ocular phenotype in the family in which it occurred.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Richards
authors.forename: Maureen
authors.initials: M
authors.lastname: Laidlaw
authors.forename: Joanne
authors.initials: J
authors.lastname: Whittaker
authors.forename: Becky
authors.initials: B
authors.lastname: Treacy
authors.forename: Harjeet
authors.initials: H
authors.lastname: Rai
authors.forename: Philip
authors.initials: P
authors.lastname: Bearcroft
authors.forename: David M
authors.initials: DM
authors.lastname: Baguley
authors.forename: Arabella
authors.initials: A
authors.lastname: Poulson
authors.forename: Alan
authors.initials: A
authors.lastname: Ang
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Martin P
authors.initials: MP
authors.lastname: Snead
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002972:Cleft Palate / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons; D015785:Eye Diseases, Hereditary / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D022821:RNA Splice Sites; D013577:Syndrome; D014822:Vitreous Body / Q000002:abnormalities* / Q000473:pathology
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; D022821:RNA Splice Sites