2. Academic Validation
  3. Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis

  • Am J Hum Genet. 2020 Jul 2;107(1):158-163. doi: 10.1016/j.ajhg.2020.05.013.
Lynn M Boyden 1,  Jing Zhou 2,  Ronghua Hu 2,  Theodore Zaki 2,  Erin Loring 1,  Jared Scott 3,  Heiko Traupe 4,  Amy S Paller 5,  Richard P Lifton 1,  Keith A Choate 6
Affiliations

Affiliations

  • 1 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 2 Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 3 Idaho Skin Surgery Center, Boise, ID 83705, USA.
  • 4 Department of Dermatology, University of Münster, 48149 Münster, Germany.
  • 5 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 6 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: [email protected].
PMID: 32516568 DOI: 10.1016/j.ajhg.2020.05.013
Abstract

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Keywords

ASPRV1; Mendelian; SASPase; de novo; dominant; epidermis; exome; ichthyosis; keratoderma; skin.

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