DOMINANT MUTATIONS IN THE TYPE-II COLLAGEN GENE, COL2A1, PRODUCE SPONDYLOEPIMETAPHYSEAL DYSPLASIA, STRUDWICK TYPE

The chondrodysplasias are a heterogeneous group of disorders characterized by abnormal growth or development of cartilage1. Current classification is based on mode of inheritance as well as clinical, histologic, and/or radiographic features2. A clinical spectrum of chondrodysplasia phenotypes, ranging from mild to perinatal lethal, is due to defects in the gene for type II collagen, COL2A1. This spectrum includes Stickler syndrome, Kniest dysplasia, spondyloepiphyseal dysplasia congenita (SEDC), achondrogenesis type II, and hypochondro-genesis3, 4. Individuals affected with these disorders exhibit abnormalities of the growth plate, nucleus pulposus, and vitreous humor1, 5, which are tissues that contain type II collagen6. The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). The phenotype was first described by Murdoch and Walker7 in 1969, and a series of 14 patients was later reported by Anderson et al.8 The observation of two affected sibs born to unaffected parents led to the classification of SEMD Strudwick as an autosomal recessive disorder. We now describe the biochemical characterization of defects in α1 (II) collagen in three unrelated individuals with SEMD Strudwick, each of which is due to heterozygosity for a unique mutation in COL2A1. Our data support the hypothesis that some cases, if not all cases, of this distinctive chondrodysplasia result from dominant mutations in COL2A1, thus expanding the clinical spectrum of phenotypes associated with this gene. © 1995 Nature Publishing Group.