Genetic loci for ventricular dilatation in the LEW/Jms rat with fetal-onset hydrocephalus are influenced by gender and genetic background.

ABSTRACT

BACKGROUND: The LEW/Jms rat strain has inherited hydrocephalus, with more males affected than females and an overall expression rate of 28%. This study aimed to determine chromosomal positions for genetic loci causing the hydrocephalus. METHODS: An F1 backcross was made to the parental LEW/Jms strain from a cross with non-hydrocephalic Fischer 344 rats. BC1 rats were generated for two specific crosses the first with a male LEW/Jms rat as parent and grandparent, [(F x L) x L], designated B group, and the second with a female LEW/Jms rat as the parent and grandparent [L x (L x F)], designated C group. All hydrocephalic and a similar number of non-hydrocephalic rats from these two groups were genotyped with microsatellite markers and the data was analyzed separately for each sex by MAPMAKER. RESULTS: The frequency of hydrocephalus was not significantly different between the two groups (18.2 and 19.9 %), but there was a significant excess of males in the B group. The mean severity of hydrocephalus, measured as the ventricle-to-brain width ratio, was ranked as B group < C group < LEW/Jms. For the both rat groups, there were several chromosomes that showed possible regions with association between phenotype and genotype significant at the 5% or 1.0% level, but none of these had significant LOD scores. For the C group with a female LEW/Jms parent, there was a fully significant locus on Chr2 with a LOD score of 3.81 that was associated almost exclusively with male rats. Both groups showed possible linkage on Chr17 and the data combined produced a LOD score of 2.71, between suggestive and full significance. This locus was largely associated with male rats with a LEW/Jms male parent. CONCLUSION: Phenotypic expression of hydrocephalus in Lew/Jms, although not X-linked, has a strong male bias. One, and possibly two chromosomal regions are associated with the hydrocephalus.