A LINKAGE STUDY WITH DNA MARKERS (D4S95, D4S115, AND D4S111) IN JAPANESE HUNTINGTON DISEASE FAMILIES

Attempts to isolate the Huntington disease (HD) gene based on its posi tion have been frustrated by apparently contradictory recombination ev ents in HD pedigrees that have predicted two non-overlapping candidate regions: 100 kb at the telomere of the short arm of chromosome 4, and a 2.2 Mb region located internally at 4p16.3. The proximal location i s also supported by the detection of a linkage disequilibrium between HD and some restriction fragment length polymorphisms (RFLPs) at the D 4S95, D4S98, and D4S127 loci. In the present study, a proximal marker D4S95 showed tight linkage to the disease locus in Japanese pedigrees (Z(max)=3.31, theta(max)=0.00), while distal markers D4S115 and D4S111 did not. Particularly, a two point linkage analysis between D4S111 an d HD yielded a lod score - 2.01 for theta = 0.015. This result leads t o the exclusion, as a possible region of localization of the HD gene, of more than 3 cM of the genome around D4S111 locus. At the same ti me our results favor aforementioned proximal location as a candidate loc ation for the HD gene.