GENETIC AND PHYSICAL MAPPING OF THE CHEDIAK-HIGASHI-SYNDROME ON CHROMOSOME 1Q42-43

The Chediak-Higashi syndrome (CHS) is a severe autosomal recessive con dition, features of which are partial oculocutaneous albinism, increas ed susceptibility to infections, deficient natural killer cell activit y, and the presence of large intracytoplasmic granulations in various cell types. Similar genetic disorders have been described in other spe cies, including the beige mouse. On the basis of the hypothesis that t he murine chromosome 13 region containing the beige locus was homologo us to human chromosome 1, we have mapped the CHS locus to a 5-cM inter val in chromosome segment 1q42.1-q42.2. The highest LOD score was obta ined with the marker D1S235 (Z(max) = 5.38; theta = 0). Haplotype anal ysis enabled us to establish D1S2680 and D1S163, respectively, as the telomeric and the centromeric flanking markers. Multipoint linkage ana lysis confirms the localization of the CHS locus in this interval. Thr ee YAC clones were found to cover the entire region in a contig establ ished by YAC end-sequence characterization and sequence-tagged site ma pping. The YAC contig contains all genetic markers that are nonrecombi nant for the disease in the nine CHS families studied. This mapping co nfirms the previous hypothesis that the same gene defect causes CHS in human and beige phenotype in mice and provides a genetic framework fo r the identification of candidate genes.