International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I17. Molecular Dissection of the Critical Region of a Mouse Preaxial Polydactyly Mutation, Hemimelic Extra Toes (Hx)

Tomoko Sagai1, Hiroshi Masuya2, Kunihiko Shimizu3, Yukari Yada1,4 and Toshihiko Shiroishi1,2
1National Institute of Genetics, Mishima, Japan; 2RIKEN Genomic Sciences Center; 3Nihon University School of Dentistry at Matsudo, Chiba, Japan; 4 Ochanomizu University)

A signaling molecule, Sonic hedgehog (Shh), is expressed in posterior limb margin designated as zone of polarizing activity (ZPA), and it controls patterning of limb along the anterior-posterior axis. Several preaxial polydactylous mouse mutations are known to exhibit ectopic expression of shh at the anterior limb margin. One of such mutants Hemimelic extra-toes (Hx) is located at the region closely linked to the shh locus in the chromosome 5. It has been argued that a mutation in the cis-regulatory region of shh may cause the Hx phenotype. A human complex poly-syndactylism that resembles to Hx phenotype has been mapped to the human syntenic region of the chromosome 7q36. It is likely that mouse Hx is an animal model for this human limb defect. Recently, Heus et al. reported many candidate genes for this human limb defect in the 7q36 region. For the last several years, we have carried out genetic and physical mapping of Hx. At present, Hx is confined to a 150 kb single BAC clone. It appeared that the mouse homologues of two ORFs that were identified as the candidates for the human limb defect are located in this BAC clone. The 5 coding region of one homologue was located in the Hx-critical region. Sequencing of RT-PCR product of this gene revealed no alteration in Hx mutant. Thus, it is possible that additional unknown gene or alternative spliced form of the same homologue is located in the Hx-critical region. Alternatively, a cis-regulatory element of the shh gene, which is located to the critical region very remote from the shh coding, may be disrupted in Hx mutation.

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