@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 {734, title = {Mutations in PERP Cause Dominant and Recessive Keratoderma.}, journal = {J Invest Dermatol}, volume = {139}, year = {2019}, month = {2019 02}, pages = {380-390}, abstract = {

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

}, issn = {1523-1747}, doi = {10.1016/j.jid.2018.08.026}, author = {Duchatelet, Sabine and Boyden, Lynn M and Ishida-Yamamoto, Akemi and Zhou, Jing and Guibbal, Laure and Hu, Ronghua and Lim, Young H and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Santos-Simarro, Fernando and de Lucas, Raul and Milstone, Leonard M and Gildenstern, Vanessa and Helfrich, Yolanda R and Attardi, Laura D and Lifton, Richard P and Choate, Keith A and Hovnanian, Alain} } @article {395, title = {Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jun 01}, pages = {978-984}, abstract = {

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

}, keywords = {Alcohol Oxidoreductases, Ceramides, Genes, Recessive, Genetic Complementation Test, Genetic Predisposition to Disease, Heterozygote, Humans, Intermediate Filament Proteins, Keratosis, Mutation, Polymorphism, Single Nucleotide, RNA Splicing, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.003}, author = {Boyden, Lynn M and Vincent, Nicholas G and Zhou, Jing and Hu, Ronghua and Craiglow, Brittany G and Bayliss, Susan J and Rosman, Ilana S and Lucky, Anne W and Diaz, Luis A and Goldsmith, Lowell A and Paller, Amy S and Lifton, Richard P and Baserga, Susan J and Choate, Keith A} } @article {289, title = {Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jan 15}, pages = {397-407}, abstract = {

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

}, keywords = {Adolescent, Child, Exome, Female, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, GTP Phosphohydrolases, Humans, Hypophosphatemia, Male, Membrane Proteins, Mutation, Nevus, Nevus, Pigmented, Osteomalacia, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, Skin, Skin Neoplasms}, issn = {1460-2083}, doi = {10.1093/hmg/ddt429}, author = {Lim, Young H and Ovejero, Diana and Sugarman, Jeffrey S and Deklotz, Cynthia M C and Maruri, Ann and Eichenfield, Lawrence F and Kelley, Patrick K and J{\"u}ppner, Harald and Gottschalk, Michael and Tifft, Cynthia J and Gafni, Rachel I and Boyce, Alison M and Cowen, Edward W and Bhattacharyya, Nisan and Guthrie, Lori C and Gahl, William A and Golas, Gretchen and Loring, Erin C and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Levy, Moise L and Collins, Michael T and Choate, Keith A} }