title: Disproportionate micromelia (Dmm) in mice caused by a mutation in the C-propeptide coding region of Col2a1.
abstract: Mice that are homozygous for the autosomal semidominant disproportionate micromelia (Dmm) mutation are characterized by disproportionate micromelia, thoracic dysplasia, and cleft palate. Chondrocytes of the epiphyseal growth plates are not organized into columns, and ultrastructural analysis reveals excessive dilation of the endoplasmic reticulum and a paucity of collagen fibrils in the extracellular matrix. To map the Dmm locus, Dmm mice were crossed with the multiple ecotropic viral (MEV) linkage testing stock. Significant linkage of Dmm to the fourteen MEV linkage markers was not observed, thereby excluding approximately 50% of the genome as candidate regions encoding Dmm. Subsequently, microsatellite markers were used to assess linkage to the nonexcluded regions of the genome, revealing tight linkage to the locus of Col2a1, the gene encoding the alpha-chains of type II collagen. alpha 1(II) collagen cDNA, synthesized with RNA from homozygotes, was cloned and sequenced, revealing a three-nucleotide deletion in the region encoding the C-propeptide globular domain. The deletion leads to the substitution of one amino acid, Asn, in the mutant for two amino acids, Lys and Thr, in the wild type. Several human chondrodysplasias with similar phenotypes to that of Dmm are associated with defects in type II collagen. Thus, mice bearing the Dmm mutation serve as a model for studying the pathogenesis of these disorders while revealing novel insights into normal skeletal morphogenesis.
authors.affiliation: Department of Zoology, Brigham Young University, Provo, Utah 84602, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Pace
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: R E
authors.initials: RE
authors.lastname: Seegmiller
authors.forename: C
authors.initials: C
authors.lastname: Teuscher
authors.forename: B A
authors.initials: BA
authors.lastname: Taylor
authors.forename: B R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002356:Cartilage / Q000002:abnormalities / Q000378:metabolism*; D002874:Chromosome Mapping; D003094:Collagen / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000473:pathology; D005796:Genes / Q000235:genetics; D008040:Genetic Linkage; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010009:Osteochondrodysplasias / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D003094:Collagen