International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


I Aubin
Institut Pasteur

1) Poirier C, 2) Muriel MP, 2) Stanescu V, 1) Guénet JL
1) Institut Pasteur, 2) Hôpital Necker – Enfants Malades

In man, Osteogenesis imperfecta (OI) is an heterogeneous group of inherited skeletal disorders resulting in general from mutations in collagen type 1 genes (COL1A1 and COL1A2). So far, in the mouse, two mutations leading to OI syndrome have been identified Mov13, a dominant allele of Col1a1 (chr 11), and oim a recessive allele of Col1a2 (chr 6). The mouse recessive mutation, fragilitas ossium (fro) is a new model for severe forms of OI unlinked to collagen defects. Fragilitas ossium (fro/fro), previously known as forelimb deformity (fld/fld), is an autosomal recessive mutation that was discovered, in 1975, in a randombred stock of mice after treatment of spermatocytes with the chemical mutagen tris(1-aziridinyl) phosphine-sulphide (ThioTEPA).This mutation, which is often lethal, is controlled by one fully penetrant recessive allele. Live homozygous mutant mice (fro/fro) display most of the features specific to OI: curved and brittled bones, small size and abnormal dentinogenesis, but have normal lifespan and fertility. The bowing of bones becomes less obvious with ageing.Genetic mapping of the fro locus was achieved by genotyping three different intercrosses involving the FRA/Pas inbred strain (segregating for fro) and MBT/Pas, MAI/Pas and SEG/Pas srains derived respectively from Mus musculus musculus or Mus spretus species. Such interspecific crosses allow the segregation of great amount of polymorphisms in the progenies. The single locus maps in the midpart of mouse chromosome 8.160 fro/fro and 430 wild type mice were genotyped with microsatellite and ESTs markers. The shortest chromosomal segment containing the fro locus could be reduced to 1,5Mb.Searching in the databases points to a ready-made BAC contig. The new molecular tools developped by the Human and Mouse Genome Sequencing Projects may speed up the study and the cloning of the causative gene and its human homolog which is obviously a candidate for some severe human forms of OI.

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