REFINED GENETIC-MAPPING OF THE DARIER LOCUS TO A LESS-THAN-1-CM REGION OF CHROMOSOME 12Q24.1, AND CONSTRUCTION OF A COMPLETE, HIGH-RESOLUTION P1 ARTIFICIAL CHROMOSOME BACTERIAL ARTIFICIAL CHROMOSOME CONTIG OF THE CRITICAL REGION

Darier disease (DD) (MIM 124200) is an autosomal dominant skin disorde r characterized by loss of adhesion between epidermal cells and by abn ormal keratinization. We present linkage analysis showing, in four fam ilies, key recombination events that refine the location of the DD loc us on chromosome 12q23-24.1 to a region of <1 cM. We have constructed a YAC/P1 artificial chromosome (PAC)/bacterial artificial chromosome ( BAC)-based physical map that encompasses this refined DD region. The m ap consists of 35 YAC, 69 PAC, 16 BAC, and 2 cosmid clones that were o rdered by mapping 54 anonymous sequence-tagged sites. The critical reg ion is estimated to be 2.4 Mb in size, with an average marker resoluti on of 37.5 kb. The refinement of the critical interval excludes the AL DH2, RPL6, PTPN11, and OAS genes, as well as seven expressed sequence tags (ESTs) previously mapped in the DD region. The three known genes (ATP2A2, PPP1CC, and SCA2) and the 10 ESTs mapped within the critical region are not obvious candidates for the DD gene. Therefore, this det ailed integrated physical, genetic, and partial transcript map provide s an important resource for the isolation of the DD gene and, possibly , other disease genes.