Mapping ofD4S98/S114/S113confines the Huntington's defect to a reduced physical region at the telomere of chromosome 4

Abstract

The dominant gene defect in Huntington's disease ( HD ) is linked to the DNA marker D4S10, near the telomere of the chromosome 4 short arm. Two other markers, D4S43 and D4S95 , are closer, but still proximal to the HD gene in 4p16.32. We have characterized a new locus, D4S114 , identified by cloning the end of a NotI fragment resolved by pulsed-field gel electrophoresis. D4S114 was localized distal to D4S43 and D4S95 by both physical and genetic mapping techniques. The ‘end’-clone overlaps a previously isolated NotI ‘linking’ clone, and is within 150 kb of a second ‘linking’ clone defining D4S113 . Restriction fragment length polymorphisms for D4S113 and D4S114 , one of which is identical to a SacI polymorphism detected by the anonymous probe pB5731B-C ( D4S98 ), were typed for key crossovers in HD and reference pedigrees. The data support the locus order D4S10-(D4S43, D4S98, D4S95)-D4S98/S114/S113 -HD-telemere. The D4S98/S114/S113 cluster therefore represents the nearest cloned sequences to HD , and provides a valuable new point for launching directional cloning strategies to isolate and characterize this disease gene.