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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

ABSTRACT: SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.

SUBMITTER: Courcet JB

PROVIDER: S-EPMC4463501 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

Courcet Jean-Benoît JB Elalaoui Siham Chafai SC Duplomb Laurence L Tajir Mariam M Rivière Jean-Baptiste JB Thevenon Julien J Gigot Nadège N Marle Nathalie N Aral Bernard B Duffourd Yannis Y Sarasin Alain A Naim Valeria V Courcet-Degrolard Emilie E Aubriot-Lorton Marie-Hélène MH Martin Laurent L Abrid Jamal Eddin JE Thauvin Christel C Sefiani Abdelaziz A Vabres Pierre P Faivre Laurence L

European journal of human genetics : EJHG 20141015 7

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reti ...[more]

PMID: 25315659

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Project description:BackgroundPachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature.ObjectivesThis review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms.MethodsWe reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK.ResultsThere are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis.ConclusionsThe progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.

Dataset Information

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

Publications

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

Similar Datasets

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