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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 158-163 |
| Number of pages | 6 |
| Journal | American journal of human genetics |
| Volume | 107 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2 2020 |
Funding
We thank the study subjects, their families, and the health care professionals whose participation made this work possible. We thank Nicholas Theodosakis, Irina Tikhonova, Christopher Castaldi, Kaya Bilguvar, James Knight, Stefanos Koutsoukos, and Richard Presland for technical contributions. This work was supported in part by the Foundation for Ichthyosis and Related Skin Types (FIRST) and the National Institutes of Health (NIH R01 AR068392 to K.A.C. and UM1 HG006504 to the Yale Center for Mendelian Genomics).
Keywords
- ASPRV1
- Mendelian
- SASPase
- de novo
- dominant
- epidermis
- exome
- ichthyosis
- keratoderma
- skin
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)