Pseudoachondroplasia and Multiple Epiphyseal.pdf

HUMAN MUTATION 19:465?478 (2002) ? 2002 Wiley-Liss, Inc. REVIEW ARTICLE Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: Mutation Review, Molecular Interactions, and Genotype to Phenotype Correlations Michael D. Briggs* and Kathryn L. Chapman Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester, UK Communicated by Iain McIntosh Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dys- plasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias. Hum Mutat 19:465?478, 2002. ? 2002 Wiley-Liss, Inc. KEY WORDS: pseudoachondroplasia; PSACH; multiple epiphyseal dysplasia; MED; cartilage oligo- meric matrix protein; COMP; type IX collagen; COL9; matrilin-3; MATN3; solute carrier member 26, member 2; SLC26A2; mutation analysis; genotype?phenotype cor- relation DATABASES: COMP ? OMIM: 600310, 132400 (EDM1), 177170 (PSACH); GDB: 344263; GenBank: XM009336 COL9A1 ? OMIM: 120210; GDB: 119794; GenBank: XM004151 COL9A2 ? OMIM: 120260, 600204 (EDM2); GDB: 138310; GenBank: NM001852 COL9A3 ? OMIM: 120270, 60096