Date: 06/12/2020

**Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis**

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis

Published:June 08, 2020DOI:https://doi.org/10.1016/j.ajhg.2020.05.013

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.

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References

- Adzhubei I.A.
- Schmidt S.
- Peshkin L.
- Ramensky V.E.
- Gerasimova A.
- Bork P.
- Kondrashov A.S.
- Sunyaev S.R.
A method and server for predicting damaging missense mutations.
Nat. Methods. 2010; 7: 248-249View in Article
- Traupe H.
- Kolde G.
- Happle R.
Autosomal dominant lamellar ichthyosis: a new skin disorder.
Clin. Genet. 1984; 26: 457-461View in Article
- Kolde G.
- Happle R.
- Traupe H.
Autosomal-dominant lamellar ichthyosis: ultrastructural characteristics of a new type of congenital ichthyosis.
Arch. Dermatol. Res. 1985; 278: 1-5View in Article
- Bernard D.
- Méhul B.
- Thomas-Collignon A.
- Delattre C.
- Donovan M.
- Schmidt R.
Identification and characterization of a novel retroviral-like aspartic protease specifically expressed in human epidermis.
J. Invest. Dermatol. 2005; 125: 278-287View in Article
- Rhiemeier V.
- Breitenbach U.
- Richter K.H.
- Gebhardt C.
- Vogt I.
- Hartenstein B.
- Fürstenberger G.
- Mauch C.
- Hess J.
- Angel P.
A novel aspartic proteinase-like gene expressed in stratified epithelia and squamous cell carcinoma of the skin.
Am. J. Pathol. 2006; 168: 1354-1364View in Article
- Matsui T.
- Kinoshita-Ida Y.
- Hayashi-Kisumi F.
- Hata M.
- Matsubara K.
- Chiba M.
- Katahira-Tayama S.
- Morita K.
- Miyachi Y.
- Tsukita S.
Mouse homologue of skin-specific retroviral-like aspartic protease involved in wrinkle formation.
J. Biol. Chem. 2006; 281: 27512-27525View in Article
- Matsui T.
- Miyamoto K.
- Kubo A.
- Kawasaki H.
- Ebihara T.
- Hata K.
- Tanahashi S.
- Ichinose S.
- Imoto I.
- Inazawa J.
- et al.
SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.
EMBO Mol. Med. 2011; 3: 320-333View in Article
- Sandilands A.
- Sutherland C.
- Irvine A.D.
- McLean W.H.
Filaggrin in the frontline: role in skin barrier function and disease.
J. Cell Sci. 2009; 122: 1285-1294View in Article
- Kelley L.A.
- Mezulis S.
- Yates C.M.
- Wass M.N.
- Sternberg M.J.
The Phyre2 web portal for protein modeling, prediction and analysis.
Nat. Protoc. 2015; 10: 845-858View in Article
- Bauer A.
- Waluk D.P.
- Galichet A.
- Timm K.
- Jagannathan V.
- Sayar B.S.
- Wiener D.J.
- Dietschi E.
- Müller E.J.
- Roosje P.
- et al.
A de novo variant in the ASPRV1 gene in a dog with ichthyosis.
PLoS Genet. 2017; 13: e1006651View in Article
- Smith F.J.
- Irvine A.D.
- Terron-Kwiatkowski A.
- Sandilands A.
- Campbell L.E.
- Zhao Y.
- Liao H.
- Evans A.T.
- Goudie D.R.
- Lewis-Jones S.
- et al.
Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
Nat. Genet. 2006; 38: 337-342View in Article
- Chavanas S.
- Bodemer C.
- Rochat A.
- Hamel-Teillac D.
- Ali M.
- Irvine A.D.
- Bonafé J.L.
- Wilkinson J.
- Taïeb A.
- Barrandon Y.
- et al.
Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.
Nat. Genet. 2000; 25: 141-142View in Article
- Blaydon D.C.
- Nitoiu D.
- Eckl K.M.
- Cabral R.M.
- Bland P.
- Hausser I.
- van Heel D.A.
- Rajpopat S.
- Fischer J.
- Oji V.
- et al.
Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion.
Am. J. Hum. Genet. 2011; 89: 564-571View in Article
- Basel-Vanagaite L.
- Attia R.
- Ishida-Yamamoto A.
- Rainshtein L.
- Ben Amitai D.
- Lurie R.
- Pasmanik-Chor M.
- Indelman M.
- Zvulunov A.
- Saban S.
- et al.
Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase.
Am. J. Hum. Genet. 2007; 80: 467-477View in Article
- List K.
- Szabo R.
- Wertz P.W.
- Segre J.
- Haudenschild C.C.
- Kim S.Y.
- Bugge T.H.
Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.
J. Cell Biol. 2003; 163: 901-910View in Article
- Karczewski K.J.
- Francioli L.C.
- Tiao G.
- Cummings B.B.
- Alföldi J.
- Wang Q.
- Collins R.L.
- Laricchia K.M.
- Ganna A.
- Birnbaum D.P.
- et al.
Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes.
bioRxiv. 2019;https://doi.org/10.1101/531210View in Article
- Crossref
- Google Scholar
- Sandilands A.
- Brown S.J.
- Goh C.S.
- Pohler E.
- Wilson N.J.
- Campbell L.E.
- Miyamoto K.
- Kubo A.
- Irvine A.D.
- Thawer-Esmail F.
- et al.
Mutations in the SASPase gene (ASPRV1) are not associated with atopic eczema or clinically dry skin.
J. Invest. Dermatol. 2012; 132: 1507-1510View in Article