title: A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene.
abstract: Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. guy.vancamp@ua.ac.be.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Rikkert L
authors.initials: RL
authors.lastname: Snoeckx
authors.forename: Nele
authors.initials: N
authors.lastname: Hilgert
authors.forename: Jenneke
authors.initials: J
authors.lastname: van den Ende
authors.forename: Hisakumi
authors.initials: H
authors.lastname: Fukuoka
authors.forename: Michio
authors.initials: M
authors.lastname: Wagatsuma
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: R M Erica
authors.initials: RM
authors.lastname: Smets
authors.forename: Filip
authors.initials: F
authors.lastname: Vanhoenacker
authors.forename: Frank
authors.initials: F
authors.lastname: Declau
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Usami
mesh_terms: D002648:Child; D024043:Collagen Type II / Q000235:genetics; D024081:Collagen Type IX / Q000235:genetics*; D024161:Collagen Type XI / Q000235:genetics; D004252:DNA Mutational Analysis; D050276:Hand Bones / Q000002:abnormalities / Q000000981:diagnostic imaging; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008437:Maxilla / Q000002:abnormalities / Q000000981:diagnostic imaging; D008875:Middle Aged; D009154:Mutation; D009216:Myopia / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D011859:Radiography; D012164:Retinal Diseases / Q000235:genetics*; D013577:Syndrome
chemical_list: C439970:COL9A1 protein, human; D024043:Collagen Type II; D024081:Collagen Type IX; D024161:Collagen Type XI