title: Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene.
abstract: Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that of the autosomal dominant disorders-Stickler and Marshall syndromes-but can be distinguished by disproportionately short limbs, severe hearing loss, and lack of ocular involvement. In one family with OSMED, a homozygous Gly-->Arg substitution has been described in COL11A2, which codes for the alpha2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of alpha2(XI) chains.
authors.affiliation: Collagen Research Unit, Biocenter, Department of Medical Biochemistry, University of Oulu, Kajaanintie 52A, FIN-90220 Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Melkoniemi
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: S
authors.initials: S
authors.lastname: Manouvrier
authors.forename: R
authors.initials: R
authors.lastname: Hennekam
authors.forename: A
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: H
authors.initials: H
authors.lastname: Kääriäinen
authors.forename: R M
authors.initials: RM
authors.lastname: Pauli
authors.forename: T
authors.initials: T
authors.lastname: van Essen
authors.forename: M L
authors.initials: ML
authors.lastname: Warman
authors.forename: J
authors.initials: J
authors.lastname: Bonaventure
authors.forename: P
authors.initials: P
authors.lastname: Miny
authors.forename: L
authors.initials: L
authors.lastname: Ala-Kokko
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018388:Codon, Terminator / Q000235:genetics; D003094:Collagen / Q000172:deficiency / Q000235:genetics*; D003241:Consanguinity; D003638:Deafness / Q000235:genetics* / Q000503:physiopathology; D004200:Diseases in Twins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011859:Radiography; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D012333:RNA, Messenger; D003094:Collagen