Localization of the Ames dwarf mutation and identification of the spasmodic and oscillator mutations.

摘要

Mouse mutants provide an opportunity to clone novel genes that are involved in specific biological processes, and provide animal models for human disease. The Ames dwarf gene, df, is involved in cell fate determination in the anterior pituitary gland. Anterior pituitary glands of df homozygotes lack three cell types; thyrotropes, somatotropes, and lactotropes. To clone the dfgene, we have constructed and characterized a 667 animal backcross with M. m. castaneus. Genetic mapping has eliminated known genes expressed during pituitary ontogeny as candidates for the df locus, and we have undertaken identification of the df gene by positional cloning. A yeast artificial chromosome (YAC) walk was initiated from markers located 0.3 cM proximal and 0.7 cM distal to df, and YAC end clones were used to walk towards df and assemble a contig consisting of 25 YACs. Although the nonrecombinant interval around df is 0.15 cM, physical mapping suggests this corresponds to greater than 1 Mb. Synteny homology predicts that the human counterpart to df is located on human Chr 5q. The cloning of the df gene will reveal an important player in the process of pituitary cytodifferentiation.;Spasmodic (spd) is a recessive mutation which results in tremor, stiffness, and a prolonged righting reflex when disturbed. Oscillator, a more severe allele of spasmodic, exhibits tremor and muscle spasms that progressively worsen, resulting in death. We constructed a backcross with M. m. castaneus that segregates spd. Initial genotyping of 148 progeny localized spd on mouse Chr 11, and eliminated three neurotransmitter receptor genes as candidates. Two additional genes, annexin VI (Anx6) and a glutamate receptor (Glr1), were eliminated by expression and sequence analysis. Comparative genetic mapping suggested that spd is the mouse counterpart to human hyperekplexia, which is caused by mutations in the