The molecular genetic analysis of the expanding pachyonychia congenita case collection

N J Wilson, E A O'Toole, L M Milstone, C D Hansen, A A Shepherd, E Al-Asadi, M E Schwartz, W H I McLean, E Sprecher, F J D Smith, N J Wilson, E A O'Toole, L M Milstone, C D Hansen, A A Shepherd, E Al-Asadi, M E Schwartz, W H I McLean, E Sprecher, F J D Smith

Abstract

Background: Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17.

Objectives: To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years.

Methods: Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced.

Results: Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105.

Conclusions: By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.

© 2014 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Figures

Fig 1
Fig 1
Clinical features of pachyonychia congenita (PC). Palmoplantar keratoderma, nail dystrophy, oral leukokeratosis and cysts in patients with PC with identified mutations.
Fig 2
Fig 2
Kyle–Doolittle hydrophilicity analysis of normal and mutant K6a. (a) Normal K6a tail domain consists of alternating hydrophobic and hydrophilic sequences compared with (b) the mutant tail domain, K6a p.Glu473GlyfsTer91, which is mainly hydrophilic.
Fig 3
Fig 3
Spectrum of mutations causing pachyonychia congenital (PC), showing the percentage of families in this study and previous publications with mutations in the five keratin genes associated with PC: KRT6A, KRT6B, KRT6C, KRT16 and KRT17.

References

    1. Jadassohn J, Lewandowski F. [Pachyonychia Congenita: Keratosis Disseminata Circumscripta (Follicularis). Tylomata. Leukokeratosis Linguae.] Berlin: Urban and Schwarzenberg; 1906.
    1. Munro CS, Carter S, Bryce S, et al. A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12–q21. J Med Genet. 1994;31:675–8.
    1. Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature. 1992;356:244–6.
    1. Vassar R, Coulombe PA, Degenstein L, et al. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell. 1991;64:365–80.
    1. Bonifas JM, Rothman AL, Epstein EH. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science. 1991;254:1202–5.
    1. Bowden PE, Haley JL, Kansky A, et al. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995;10:363–5.
    1. McLean WHI, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9:273–8.
    1. Smith FJD, Jonkman MF, van Goor H, et al. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet. 1998;7:1143–8.
    1. Wilson NJ, Messenger AG, Leachman SA, et al. Keratin K6c mutations cause focal palmoplantar keratoderma. J Invest Dermatol. 2010;130:425–9.
    1. McLean WH, Hansen CD, Eliason MJ, et al. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011;131:1015–7.
    1. Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129:705–33.
    1. Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006;174:169–74.
    1. Steinert PM, Parry DA. Intermediate filaments: conformity and diversity of expression and structure. Annu Rev Cell Biol. 1985;1:41–65.
    1. Steinert PM, Yang JM, Bale SJ, Compton JG. Concurrence between the molecular overlap regions in keratin intermediate filaments and the locations of keratin mutations in genodermatoses. Biochem Biophys Res Commun. 1993;197:840–8.
    1. Smith FJ, Liao H, Cassidy AJ, et al. The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:21–30.
    1. Wilson NJ, Leachman SA, Hansen CD, et al. A large mutational study in pachyonychia congenita. J Invest Dermatol. 2011;131:1018–24.
    1. Szeverenyi I, Cassidy AJ, Chung CW, et al. The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat. 2008;29:351–60.
    1. Fu T, Leachman SA, Wilson NJ, et al. Genotype–phenotype correlations among pachyonychia congenita patients with K16 mutations. J Invest Dermatol. 2011;131:1025–8.
    1. Haber RM, Rose TH. Autosomal recessive pachyonychia congenita. Arch Dermatol. 1986;122:919–23.
    1. van Steensel MAM, Jonkman MF, van Geel M, et al. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol. 2003;121:1035–8.
    1. Rickman L, Imrak D, Stevens HP, et al. N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet. 1999;8:971–6.
    1. Smith FJ, Wilson NJ, Moss C, et al. Compound heterozygous mutations in desmoplakin cause skin fragility and woolly hair. Br J Dermatol. 2012;166:894–6.
    1. Frojmark AS, Schuster J, Sobol M, et al. Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet. 2011;88:852–60.
    1. Wilson NJ, Hansen CD, Azkur D, et al. Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy – expanding the differential diagnosis for pachyonychia congenita. J Dermatol Sci. 2013;70:58–60.
    1. Armstrong DK, McKenna KE, Purkis PE, et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet. 1999;8:143–8.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe