PYCNODYSOSTOSIS - REFINED LINKAGE AND RADIATION HYBRID ANALYSES REDUCE THE CRITICAL REGION TO 2 CM AT 1Q21 AND MAP-2 CANDIDATE GENES

Pycnodysostosis (PKND) is a rare, autosomal recessive skeletal dysplas ia, which has been mapped previously to a 4-cM interval between D1S442 to D1S305 at chromosome 1q21. Only D1S498 did not recombine with the disease locus in a large, consanguineous Arab family with PKND. In the present studies, five new Genethon markers (D1S2343, D1S2344, D1S2345 , D1S2346, and D1S2347) were tested against DNA from this family and a gainst the Stanford G3 diploid radiation hybrid panel. The results per mitted ordering of some loci previously mapped at no recombinant dista nce: (D1S498/D1S2347)-(D1S2343/D1S2345)-D1S2346-D1S305. The PKND criti cal region was refined to the 2-cM interval from D1S2344 to D1S2343/D1 S2347. In addition, sequence-tagged sites were developed for the two P KND candidate genes, IL6R and MCL1. Use of radiation hybrids revealed that IL6R was tightly linked to D1S305, excluding it from the PKND cri tical region. MCL1 was most tightly linked to D1S498 and D1S2347, plac ing it within the critical region.