2. Academic Validation
  3. Mutations in PERP Cause Dominant and Recessive Keratoderma

Mutations in PERP Cause Dominant and Recessive Keratoderma

  • J Invest Dermatol. 2019 Feb;139(2):380-390. doi: 10.1016/j.jid.2018.08.026.
Sabine Duchatelet 1,  Lynn M Boyden 2,  Akemi Ishida-Yamamoto 3,  Jing Zhou 4,  Laure Guibbal 1,  Ronghua Hu 4,  Young H Lim 5,  Christine Bole-Feysot 6,  Patrick Nitschké 7,  Fernando Santos-Simarro 8,  Raul de Lucas 9,  Leonard M Milstone 4,  Vanessa Gildenstern 10,  Yolanda R Helfrich 11,  Laura D Attardi 12,  Richard P Lifton 2,  Keith A Choate 13,  Alain Hovnanian 14
Affiliations

Affiliations

  • 1 Laboratory of Genetic Skin Diseases, INSERM Imagine Institute, Paris, France; University Paris Descartes, Paris, France.
  • 2 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 3 Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
  • 4 Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 5 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 6 University Paris Descartes, Paris, France; Genomic Platform, INSERM Imagine Institute, Paris, France.
  • 7 University Paris Descartes, Paris, France; Bioinformatics Platform, INSERM Imagine Institute, Paris, France.
  • 8 Institute of Medical and Molecular Genetics, La Paz University Hospital, Madrid, Spain.
  • 9 Department of Dermatology, Hospital Universitario La Paz, Madrid, Spain.
  • 10 Phoenix Children's Hospital, Phoenix, Arizona, USA.
  • 11 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
  • 12 Departments of Radiation Oncology and Genetics, Stanford University School of Medicine, Stanford, California, USA.
  • 13 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address: [email protected].
  • 14 Laboratory of Genetic Skin Diseases, INSERM Imagine Institute, Paris, France; University Paris Descartes, Paris, France; Department of Genetics, Necker-Enfants Malades Hospital, Paris, France. Electronic address: [email protected].
PMID: 30321533 DOI: 10.1016/j.jid.2018.08.026
Abstract

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

Figures