title: Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation ofKRT83and is allelic with dominant monilethrix.
abstract: 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.
  
  
  
  To identify the gene underlying autosomal recessive PSEK in a large Pakistani kindred.
  
  
  
  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.
  
  
  
  Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) inKRT83, 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.
  
  
  
  At least some cases of PSEK result from loss-of-function mutations inKRT83. Heterozygous missense substitutions inKRT83have 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 theKRT83gene. Together, these findings indicate that different types of mutations inKRT83can result in quite different skin and hair phenotypes.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.|Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Khadim
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Zaib-Un-Nisa
authors.initials: ZU
authors.lastname: Mughal
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Falak Sher
authors.initials: FS
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Ferrara
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
mesh_terms: D000483:Alleles; D056266:Erythrokeratodermia Variabilis / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D006197:Hair / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053564:Keratins, Hair-Specific / Q000235:genetics*; D053531:Keratins, Type II / Q000235:genetics*; D008297:Male; D056734:Monilethrix / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: C507602:KRT83 protein, human; D053564:Keratins, Hair-Specific; D053531:Keratins, Type II
keywords: Dermatology; Genome-wide; Molecular genetics