DISPROPORTIONATE MICROMELIA (DMM) IN MICE CAUSED BY A MUTATION IN THEC-PROPEPTIDE CODING REGION OF COL2A1

Mice that are homozygous for the autosomal semidominant disproportiona te micromelia (Dmm) mutation are characterized by disproportionate mic romelia, thoracic dysplasia, and cleft palate. Chondrocytes of the epi physeal growth plates are not organized into columns, and ultrastructu ral analysis reveals excessive dilation of the endoplasmic reticulum a nd a paucity of collagen fibrils in the extracellular matrix. To map t he Dmm locus, Dmm mice were crossed with the multiple ecotropic viral (MEV) linkage testing stock. Significant linkage of Dmm to the fourtee n MEV linkage markers was not observed, thereby excluding approximatel y 50% of the genome as candidate regions encoding Dmm. Subsequently, m icrosatellite markers were used to assess linkage to the nonexcluded r egions of the genome, revealing tight linkage to the locus of Col2a1, the gene encoding the alpha-chains of type II collagen. alpha 1(II) co llagen cDNA, synthesized with RNA from homozygotes, was cloned and seq uenced, revealing a three-nucleotide deletion in the region encoding t he C-propeptide globular domain. The deletion leads to the substitutio n of one amino acid, Asn, in the mutant for two amino acids, Lys and T hr, in the wild type. Several human chondrodysplasias with similar phe notypes to that of Dmm are associated with defects in type II collagen . Thus, mice bearing the Dmm mutation serve as a model for studying th e pathogenesis of these disorders while revealing novel insights into normal skeletal morphogenesis. (C) 1997 Wiley-Liss, Inc.