Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.
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.
['Boyden|Lynn M|LM|', 'Zhou|Jing|J|', 'Hu|Ronghua|R|', 'Zaki|Theodore|T|', 'Loring|Erin|E|', 'Scott|Jared|J|', 'Traupe|Heiko|H|', 'Paller|Amy S|AS|', 'Lifton|Richard P|RP|', 'Choate|Keith A|KA|']
D016282:Aspartic Acid Endopeptidases D000091344:Filaggrin Proteins D040941:Heredity D006579:Heterozygote D006801:Humans D017490:Ichthyosis, Lamellar D007381:Intermediate Filament Proteins D020125:Mutation, Missense D010641:Phenotype D012871:Skin Diseases D000073359:Whole Exome Sequencing
ASPRV1 ichthyosis skin exome dominant Mendelian keratoderma SASPase de novo epidermis