Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia

✍ Scribed by John F. Bateman; Richard Wilson; Susanna Freddi; Shireen R. Lamandé; Ravi Savarirayan

• Book ID: 102263933
• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 318 KB
• Volume: 25
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20183

✦ Synopsis

Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1). Thirty heterozygous mutations have been described, about equally divided into two mutation types, missense mutations, and mutations that introduce premature termination signals. The COL10A1 mutations are clustered (33/36) in the 3' region of exon 3, which codes for the C-terminal NC1 trimerization domain. The effect of COL10A1 missense mutations have been examined by in vitro expression and assembly assays and cell transfection studies, which suggest that a common consequence is the disruption of collagen X trimerization and secretion, with consequent intracellular degradation. The effect of COL10A1 nonsense mutations in cartilage tissue has been examined in two patients, demonstrating that the mutant mRNA is completely removed by nonsense mediated mRNA decay. Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD.