GENETICS OF PRIMARY AND TIMING EFFECTS IN THE MND MOUSE

The mnd mouse shows a spontaneous adult-onset hereditary neurological disease, with motor abnormality by 6 months of age, progressing to sev ere spastic paralysis and premature death, The disease is autosomal re cessive, with heterozygote effects seen under stress. It maps to mouse chromosome (chr) 8, Histopathology with Nissl stains documents substa ntial abnormalities of upper and lower motor neurons, and there is ret inal degeneration beginning in the first month, even without light exp osure, Increasing levels of autofluorescent lipopigment are found in b oth neuronal and non-neuronal tissues as the mnd mice age, Recently, N CL-like inclusions and accumulating subunit c have also been described . When mnd is outcrossed to the AKR/J genetic background, ca, 40% of t he mnd/mnd F2 progeny show early onset (onset by 4.5-5 months and deat h by 7 months.) This accelerated timing effect seems to be strain-spec ific, and unlinked to the mnd gene itself, Our current working hypothe sis is that the timing effect is due to 2 or 3 unlinked dominant genes with incomplete penetrance at any single locus. In a combined RFLP/PC R fragment genetic analysis, the strongest deviation from the expected ratio of AKR vs B6 alleles occurs with markers on proximal half of ch r 1, Additional loci on chrs 5 and 10 may also be involved, The mechan ism of interaction of these modifying genes with the primary mnd gene may offer new therapeutic avenues. (C) 1995 Wiley-Liss,Inc.