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.

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

“…Pachyonychia congenita (PC) is a rare condition typified by marked nail dystrophy, palmoplantar keratoderma (PPK), oral lesions, and cystic skin lesions (7). PC is caused by mutations affecting either the type II keratin paralogs KRT6A, KRT6B, or KRT6C or the related type I keratin KRT16 or KRT17 genes (7,8).…”

“…PC is caused by mutations affecting either the type II keratin paralogs KRT6A, KRT6B, or KRT6C or the related type I keratin KRT16 or KRT17 genes (7,8). Consistent with the clinical presentation of PC, these keratin genes are normally expressed in ectoderm-derived epithelial appendages and in the thicker epidermis of palms and soles, but not in interfollicular epidermis (9).…”

The molecular genetic analysis of the expanding pachyonychia congenita case collection

“…All primers were checked for single nucleotide polymorphisms using Diagnostic SNPCheck (www.ngrl.org.uk/ Manchester), and some have been modified since our previous publications to increase specificity (Table S1). 9,15,16 For amplification of larger fragments, Takara LA Taq polymerase and buffer (Takara Bio Europe/Clontech, 78100 Saint-Germainen-Laye, France) was used; for smaller polymerase chain reaction (PCR) reactions, HotStarTaq DNA Polymerase and buffer system (Qiagen, Crawley, U.K.) was used according to the manufacturer's instructions. Specific PCR conditions for each primer set are available on request.…”

RNA Interference-Based Therapeutics: Harnessing the Powers of Nature

“…Pachyonychia congenita (PC) is an extremely rare, highly disabling autosomal dominant inherited disorder with less than a few thousand cases worldwide (Kaspar, 2005). This disorder which affects nails, skin, oral mucosa, hair and teeth (Smith et al, 2005), causes painful plantar calluses for which no satisfactory treatment is currently available. PC is caused by mutations in either keratin K6, K16 or K17, including small deletions and single nucleotide changes.…”