Mapping of a novel locus for an autosomal recessive form of palmoplantar keratoderma on chromosome 3q27.2-q29

P>Background Palmoplantar keratodermas (PPKs) are a group of highly heterogeneous diseases causing hyperkeratosis of the palms and soles. They can be inherited in an autosomal recessive, dominant, mitochondrial or possibly X-linked recessive fashion. The present study describes clinical and molecular genetic analysis of a consanguineous Pakistani family showing a severe form of PPK inherited in an autosomal recessive manner. Objectives To map the gene responsible for an autosomal recessive form of PPK. Methods Human genome scan using polymorphic microsatellite markers was performed to localize the disease gene. Eleven candidate genes, located in the linkage interval, were screened to identify the potential sequence variants. Results All five affected members of the family showed severe bilateral involvement of palms and soles with minor nail involvement, severe fissuring with bleeding, painful walking, and problems in grasping. Linkage analysis in the family mapped a novel locus for the disease on chromosome 3q27.2-q29. The candidate region flanked by markers D3S1530 and D3S1272 spans 28 center dot 22 cM, which corresponds to a physical distance of 11 center dot 63 Mb. The maximum two-point LOD score of 3 center dot 13 at theta = 0 center dot 00 was obtained with marker D3S2748 along the disease locus. DNA sequence analysis of 11 candidate genes, located in the linkage interval, failed to detect functional sequence variants. Conclusions A novel locus for an autosomal recessive form of PPK was mapped on chromosome 3q27.2-q29 in a consanguineous Pakistani family. Failure to detect pathogenic sequence variants in the 11 candidate genes suggests either that the variants are located in the regulatory regions of the genes or that another unknown gene, responsible for the disease, is present in the region.