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 KRT83, 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 KRT83. Heterozygous missense substitutions in KRT83 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 KRT83 gene. Together, these findings indicate that different types of mutations in KRT83 can result in quite different skin and hair phenotypes.
- Molecular genetics
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Contributors KS, MA, Z-u-NM and FSK collected patient samples and patient data. KS carried out all laboratory analyses, analysed the data and wrote the first draft of the manuscript. WA conceived the project, supervised KS, MA, Z-u-NM, FSK and approved the final manuscript. TMF assisted with exome sequencing. RAS supervised KS in exome sequencing, autozygosity mapping and data analysis, and wrote the final manuscript. All authors approved the final manuscript.
Funding This work was supported by a grant from the Higher Education Commission of Pakistan (to KS) and Skin Diseases Research Center grant AR057212 from the National Institutes of Health (Molecular Genetic Analysis Core; to RAS).
Competing interests None declared.
Ethics approval COMIRB (University of Colorado Denver) and Institutional Review Board (Quaid-i-Azam University).
Provenance and peer review Not commissioned; externally peer reviewed.