International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B15. Positional Cloning of Zitter, the Gene Responsible for Hypomyelination and Vacuolation in the Central Nervous System

Takashi Kuramoto1, Kazuhiro Kitada2, Toshihide Inui3, Yoshifumi Sasaki3, Kazumi Ito4, Takao Hase5, Saburo Kawaguchi5, Yoshihiro Ogawa6, Kazuwa Nakao6, Gregory S Barsh7, Minako Nagao1, Toshikazu Ushijima1, Tadao Serikawa2
1Carcinogenesis Div., Natl. Cancer Center Res. Inst., 2Inst. of Lab. Anim., 5Dept. of Integrative Brain Sci., 6Dept. of Med. and Clin. Sci., Grad. Sch. of Med., Kyoto Univ. 3Safety Res. Lab., Tanabe Seiyaku Co. Ltd., 4YS New Tech. Inst. Inc., and 7Dept. of Pediatrics and Genet. and the HHMI, Stanford Univ. School of Med.

The zitter rat was found in a colony of Sprague Dawley rats in 1982 as a spontaneous mutant that demonstrated body tremor and flaccid paresis of the hind limbs. The main neuropathological findings in the central nervous system were hypomyelination and vacuolation. These phenotypes were inherited in an autosomal recessive manner, and the causative gene, zitter (zi), was mapped to rat chromosome 3q35. By positional cloning, we identified the zitter mutation as an 8-bp deletion at the splice donor site of the mahogany (mg) gene, which was originally cloned in mice and is known to darken agouti coat color and antagonize obesity and hyperphagia observed in the agouti-lethal-yellow mutant mice. The mg mutation in zitter mutant rats also darkened coat color when introduced into agouti rats. It was also demonstrated that mice carrying the homozygous mg mutation exhibit hypomyelination and vacuolation in the CNS associated with body tremor. Transgenic complementation with the wild-type mg gene in zitter mutant rats restored normal myelination and architecture of the CNS, with disappearance of tremor. These findings conclude that the zitter/mahogany gene plays critical roles in myelination in the CNS and hair pigmentation.

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