INSERTIONAL MUTATION OF THE MOTOR END-PLATE DISEASE (MED) LOCUS ON MOUSE CHROMOSOME-15

Homozygous transgenic mice from line A4 have an early-onset progressiv e neuromuscular disorder characterized by paralysis of the rear limbs, muscle atrophy, and lethality by 4 weeks of age. The transgene insert ion site was mapped to distal chromosome 15 close to the locus motor e ndplate disease (med). The sequence of mouse DNA flanking the insertio n site junctions was determined. A small (<20 kb) deletion was detecte d at the insertion site, with no evidence of additional rearrangement of the chromosomal DNA. Noncomplementation of the transgene-induced mu tation and med was demonstrated in a cross with med(J)/+ mice. The new allele is designated med(TgNA4Bs) (med(tg)). The homologous human loc us MED was assigned to chromosome 12. Synaptotagmin 1 and contactin 1 were eliminated as candidate genes for the med mutation. The transgene -induced allele provides molecular access to the med gene, whose funct ion is required for synaptic transmission at the neuromuscular junctio n and long-term survival of cerebellar Purkinje cells. (C) 1995 Academ ic Press, Inc.