F19 LOCALIZATION OF THE GENE FOR HYPOTRICHOSIS CONGENITA MARIE UNNA - LINKAGE ANALYSIS AND CONTIG CONSTRUCTION

Van Steensel M¹, Van Geel M¹, Smith FJ², Coleman CM², McLean WHI², Steijlen PM²; ¹Department of Dermatology, University of Nijmegen, Nijmegen, The Netherlands, ²Epithelial Genetics Group, Ninewells Hospital, Dundee, United Kingdom

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder. Onset is in childhood with worsening during puberty. Linkage analysis was performed in a large Dutch family using 400 microsatellite markers. Linkage was detected with marker D8S258, and further analysis with additional markers in this and an additional British family gave a combined maximum two-point LOD score of 13.42 with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Several candidate genes have been mapped to this interval. One of these is the hairless (hr) gene, mutations of which cause the recessive disorder atrichia universalis. By cDNA and genomic sequencing we excluded the hr gene as a candidate gene. The possibility of mutations in undiscovered exons was excluded by using combed FISH. We placed the hr gene _~160 kb outside the candidate interval. Other genes that were evaluated include vinexin, FEZ1, KILLER-2, Early Growth Response gene 3 and lysosomal apyrase. No mutations were detected in the genes evaluated so far.

We have now constructed a BAC contig using a combination of probe hybridization, PCR-based BAC library screening and in silico BAC end mapping. Using the data we have obtained from this effort, we have now limited the candidate disease region to _~0.5 cM. We have identified a number of candidate genes in the contig and are now evaluating those for mutations in patients.