The molecular pathogenesis of Schmid metaphyseal chondrodysplasia

Abstract

Schmid metaphyseal chondrodysplasia (SMCD; MIM 156500) is an autosomal dominant skeletal dysplasia characterized clinically by short stature and genu varum and radiographically by metaphyseal irregularities and coxa vara. The condition results from heterozygous mutations in the gene for type X collagen, whose expression is restricted to the hypertrophic chondrocytes of growth plate cartilage. The molecular pathogenesis of SMCD is unresolved with haploinsufficient, dominant negative and dominant gain of function models being proposed. We present a large kindred with typical SMCD in which the type X collagen mutation was characterized at both the genomic and tissue (growth plate) level. The mutation was a single nucleotide substitution in the carboxyl-terminal NC1 domain, changing a Trp⁶¹¹ codon (TGG) to a stop codon (TAG). Analysis of expression of normal and mutant allele transcripts in growth plate cartilage by RT-PCR, sequencing and single nucleotide primer extension assay (SNuPE) revealed <1% mutant mRNA. The phenomenon of nonsense-mediated mRNA decay is most likely responsible for the lack of mutant mRNA transcripts in growth plate cartilage. In addition, electron microscopic analysis of affected growth plate cartilage revealed changes in the organization of type II collagen fibrils compared with control cartilage. These data support the findings in the only other patient with SCMD who has been studied by direct analysis of cartilage. These studies provide strong evidence to indicate that a functionally null allele, leading to haploinsufficiency of type X collagen, is the molecular basis of SMCD in at least a proportion of cases.