HEREDITARY SPASTIC PARAPLEGIA LINKED TO CHROMOSOME 15Q - ANALYSIS OF CANDIDATE GENES

We previously reported an extended kindred with autosomal dominant unc omplicated hereditary spastic paraplegia (HSP) and found close linkage between the disorder and microsatellite polymorphisms on chromosome 1 5q. Multipoint linkage analysis reached a maximum LOD score (10.16) be tween D15S128 and D15S156, a region that includes genes encoding alpha 5 and beta 3 subunits of GABA(A) receptor. Theoretically, abnormal GA BA-mediated neurotransmission could produce spasticity and possibly ot her changes of HSP. We used genetic linkage analysis to evaluate these two HSP candidate genes and observed obligate recombinants for polymo rphisms immediately adjacent to (or within untranslated regions of) ge nes encoding alpha 5 and beta 3 GABA(A) receptor subunits. Although th ese genes are linked tightly to the HSP locus, our findings conclusive ly exclude these genes from being responsible for HSP in this kindred.