Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of and is allelic with dominant monilethrix.

BACKGROUND

Progressive symmetric erythrokeratoderma (PSEK) is a rare skin disorder characterised by symmetrically distributed demarcated hyperkeratotic plaques, often with associated palmoplantar hyperkeratosis, with new plaques appearing over time. Most cases are inherited in an autosomal dominant manner, although a few cases exhibit apparent autosomal recessive inheritance.

OBJECTIVE

To identify the gene underlying autosomal recessive PSEK in a large Pakistani kindred.

METHODS

We first carried out autozygosity mapping using microsatellite markers in candidate regions of the genome. We then carried out exome sequencing of five family members, autozygosity mapping and mutation analysis using the exome data and verification by Sanger sequencing.

RESULTS

Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in , which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin.

CONCLUSIONS

At least some cases of PSEK result from loss-of-function mutations in . Heterozygous missense substitutions in have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the gene. Together, these findings indicate that different types of mutations in can result in quite different skin and hair phenotypes.