@article {921, title = {Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {158-163}, 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 = {Aspartic Acid Endopeptidases, Heredity, Heterozygote, Humans, Ichthyosis, Lamellar, Intermediate Filament Proteins, Mutation, Missense, Phenotype, Skin Diseases, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.013}, author = {Boyden, Lynn M and Zhou, Jing and Hu, Ronghua and Zaki, Theodore and Loring, Erin and Scott, Jared and Traupe, Heiko and Paller, Amy S and Lifton, Richard P and Choate, Keith A} } @article {747, title = {Mutations in KRT10 in epidermolytic acanthoma.}, journal = {J Cutan Pathol}, volume = {47}, year = {2020}, month = {2020 Jun}, pages = {524-529}, abstract = {

BACKGROUND: Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA.

METHODS: Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis.

RESULTS: DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10.

CONCLUSIONS: Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.

}, keywords = {Acanthoma, Adult, Aged, Aged, 80 and over, Female, Genomics, Humans, Hyperkeratosis, Epidermolytic, Ichthyosis Bullosa of Siemens, Keratin-10, Keratins, Male, Middle Aged, Mutation, Skin Neoplasms, Whole Exome Sequencing}, issn = {1600-0560}, doi = {10.1111/cup.13664}, author = {Cheraghlou, Shayan and Atzmony, Lihi and Roy, Simon F and McNiff, Jennifer M and Choate, Keith A} } @article {639, title = {Keratoacanthoma Shares Driver Mutations with Cutaneous Squamous Cell Carcinoma.}, journal = {J Invest Dermatol}, volume = {136}, year = {2016}, month = {2016 08}, pages = {1737-1741}, keywords = {Aged, Aged, 80 and over, Biomarkers, Tumor, Biopsy, Carcinoma, Squamous Cell, Cohort Studies, Diagnosis, Differential, Exome, Female, Humans, Keratoacanthoma, Loss of Heterozygosity, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Skin, Skin Neoplasms, Whole Exome Sequencing}, issn = {1523-1747}, doi = {10.1016/j.jid.2016.04.002}, author = {Lim, Young H and Fisher, Jonathan M and Bosenberg, Marcus W and Choate, Keith A and Ko, Christine J} }