title: The genetic basis of pachyonychia congenita.
abstract: In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.
authors.affiliation: Epithelial Genetics Group, Human Genetics Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. f.j.d.smith@dundee.ac.uk
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Smith
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cassidy
authors.forename: Arlene
authors.initials: A
authors.lastname: Stewart
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hamill
authors.forename: Pamela
authors.initials: P
authors.lastname: Wood
authors.forename: Iris
authors.initials: I
authors.lastname: Joval
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Erik
authors.initials: E
authors.lastname: Björck
authors.forename: Faith
authors.initials: F
authors.lastname: Callif-Daley
authors.forename: Gerald
authors.initials: G
authors.lastname: Pals
authors.forename: Paul
authors.initials: P
authors.lastname: Collins
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D007644:Darier Disease / Q000151:congenital / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000235:genetics*; D005260:Female; D006801:Humans; D007633:Keratins / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000151:congenital / Q000235:genetics*; D008297:Male; D009154:Mutation; D009264:Nails, Malformed / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D007633:Keratins; D004247:DNA