title: A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy.
abstract: Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log(10) odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription-PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of alpha3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, G-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
authors.affiliation: Department of Medicine (Genetics), Children's Hospital, Boston, MA 02115, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: G F
authors.initials: GF
authors.lastname: Cox
authors.forename: F
authors.initials: F
authors.lastname: Shapiro
authors.forename: J J
authors.initials: JJ
authors.lastname: Wu
authors.forename: C A
authors.initials: CA
authors.lastname: Feener
authors.forename: T G
authors.initials: TG
authors.lastname: Thompson
authors.forename: D C
authors.initials: DC
authors.lastname: Anthony
authors.forename: D R
authors.initials: DR
authors.lastname: Eyre
authors.forename: B T
authors.initials: BT
authors.lastname: Darras
authors.forename: L M
authors.initials: LM
authors.lastname: Kunkel
mesh_terms: D002356:Cartilage / Q000473:pathology; D002648:Child; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D003094:Collagen / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D003094:Collagen