Phenotypic and Genetic Analysis of the Hindshaker Mutation

[摘要] Hindshaker (hsh) is a novel spontaneous murine mutation with autosomal recessive inheritance. Homozygous animals of both sexes exhibited a tremor of the hind end which commenced at about 2 weeks of age and largely disappeared in animals older than 6 weeks. The severity of tremor varied between mice of the same age and a small proportion did not develop a phenotype at all. Seizures, infertility and premature death were not features of the mutation. There was hypomyelination affecting predominantly the spinal cord, although optic nerves and brain were involved to a much lesser degree. The defect of thinly myelinated and naked axons was maximal at 20 days and largely resolved with time so that in the adult, most axons were myelinated. Myelin appeared structurally normal and immunocytochemistry indicated the presence of a panel of myelin proteins. Although distribution of oligodendrocytes in the spinal cord was similar to normal, hypomyelination appeared to be due, at least in part, to a paucity of mature oligodendrocytes that was most profound in the spinal cord. The partial resolution of the myelin deficit was concomitant with an increase in the number of these cells. No ultrastructural abnormalities were found in hsh oligodendrocytes and in vitro studies failed to reveal any differences between the differentiation of O-2A progenitors obtained from hsh and control mice. No marked astrocytosis was apparent although a microgliosis was detected in older animals. Taken together, the evidence suggests that the hsh mutation does not involve a major structural protein but more probably perturbs an aspect of oligodendrocyte development. The first stage of genetic mapping was undertaken using microsatellite markers and an intersubspecific (CAST/Ei) and two interstrain backcrosses (C57BL/6J and BALB/cJ). Incomplete penetrance and variation in the expression of the phenotype occurred on these genetic backgrounds due to the action of specific alleles at other non-disease loci. One such modifying locus was identified on proximal chromosome 17. The hsh gene was mapped to a 2cM interval in the middle of chromosome 3; three flanking and five intervening microsatellite markers were identified on a backcross population of 184 mice. There were no obvious candidate genes found on examination of composite genetic maps although Cnp2 apparently lies 2cM proximal to the interval of interest and remains an interesting contender. Further fine mapping now awaits the generation of vital recombination breakpoints to delimit the hsh gene to a sufficiently small interval for positional cloning by contig construction.

[发布机构] University:University of Glasgow

[关键词] Genetics