Refined Genetic Mapping of the Darier Locus to a !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 autosomaldominant skin disorder characterized by loss of adhesionbetween epidermal cells and by abnormal keratinization.We present linkage analysis showing, in four families,key recombination events that refine the location of theDD locus on chromosome 12q23-24.1 to a region of!1 cM. We have constructed a YAC/P1 artificialchromosome (PAC)/bacterial artificial chromosome(BAC)–based physical map that encompasses this refinedDD region. The map consists of 35 YAC, 69 PAC, 16BAC, and 2 cosmid clones that were ordered by mapping54 anonymous sequence-tagged sites. The critical regionis estimated to be 2.4 Mb in size, with an average markerresolution of 37.5 kb. The refinement of the critical intervalexcludes the ALDH2, RPL6, PTPN11, and OASgenes, as well as seven expressed sequence tags (ESTs)previously mapped in the DD region. The three knowngenes (ATP2A2, PPP1CC, and SCA2) and the 10 ESTsmapped within the critical region are not obvious candidatesfor the DD gene. Therefore, this detailed integratedphysical, genetic, and partial transcript map providesan important resource for the isolation of the DDgene and, possibly, other disease genes