Identification of a Locus for Punctate Palmoplantar Keratodermas at Chromosome 8q24.13–8q24.21

Abstract

Punctate palmoplantar keratodermas (PPK) is a rare autosomal dominant cutaneous disorder characterized by numerous hyperkeratotic papules that are irregularly distributed on the palms and soles. The genetic basis for this disease is unknown. We performed a genome-wide search in two Chinese families with punctate PPK to map the chromosome location of the responsible gene. We identified a locus at chromosome 8q24.13-8q24.21 with a cumulative maximum two-point LOD score of 5.41 at markers D8S1793 and D8S1774 (at recombination fraction theta=0.00). Haplotype analysis indicated that the disease gene is located within 9.20 cM region between markers D8S1804 and D8S1720. It is the first locus identified for the punctate PPK. This study provides a map location for isolation of a disease gene-causing punctate PPK.

Exome sequencing identifies aCOL14A1mutation in a large Chinese pedigree with punctate palmoplantar keratoderma

“…A novel variant candidate for disease-related pathogenic mutation was defined as one that exclusively existed in all the patients but did not appear in the controls of the family as well as in the databases including dbSNP129, eight HapMap12 and 1000 Genomes. Assuming the pathogenic mutation would have dominant effect and be close to the linkage region we previously reported,6 we identified a missense mutation in COL14A1 (NM_021110.1:exon37:c.4505C→T:p.Pro1502Leu) that is, located within the critical region of linkage at chromosome 8q24.13-8q24.21 (table 3). 6 We selected COL14A1 as the most likely candidate causal gene for PPPK for further validation analysis.…”

“…One affected member (II10) in PPPK703 developed colonic adenocarcinoma when she was 35-years-old. The members of this family were diagnosed by experienced clinical dermatologists based on the clinical presentation of punctate keratoses 6. The clinical manifestation of the proband and her father from PPPK703 were characterised by multiple punctuate hyperkeratotic papules over the surface of the palms and soles (figure 1).…”

“…In addition, PPPK has been reported to be associated with malignancies such as breast cancer, prostatic carcinoma, Hodgkin's disease, colonic adenocarcinomas and metastatic non-small-cell carcinoma of the lung 4 5. Three candidate regions, 15q22-15q24,3 8q24.13-8q24.216 and 15q22.2-15q22.31,7 were identified for PPPK by linkage study. However, the causal genes for this disease remain yet elusive.…”

“…Recently, multiple causative gene mutations of monogenic diseases have been successfully discovered by using this approach 10–12. In this study, we subjected the exomes of six individuals from a large Chinese family with PPPK, in which disease locus was previously mapped at 8q24.13-8q24.21 by our group,6 to massive parallel sequencing to search for causal gene and pathogenic mutations for PPPK.…”

Hereditary Palmoplantar Keratosis

“…Two punctate PPK loci have been found to map to 15q22-15q24 and to 8q24.13-8q24.21 [22,23]. Treatment includes keratolytics, topical salicylic acid, mechanical debridement, excision, and topical and systemic retinoids.…”