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

Abstract

9SASH1 (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.1849G4A; 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.

SASH1, a new potential link between smoking and atherosclerosis

“…We found that SASH1 knockdown increase both proliferation and migration in HAECs. This result is in accordance with the literature, as SASH1 knockdown increases proliferation and migration in various human cancer cell lines 104,109,108 , and a SASH1 variant (c.1849G>A; p.Glu617Lys) increases proliferation of human fibroblasts 115 . In accordance with our proliferation results, CCND1 and CCND3 were found to be up-regulated at the protein level following SASH1 knockdown.…”

“…Recently, SASH1 expression has been linked to a number of diseases such as pre-ecclampsia 149 , Alzheimer disease 150 , colorectal and breast cancer 133,135,136 , skin carcinoma 151 and Dyschromatosis universalis hereditaria (DUH) 141 . While little is known about the role of SASH1 in the vascular physiopathology, an in vitro study has reported SASH1 to be up-regulated following VEGF receptor blockade in human pulmonary microvascular endothelial cells 152 .…”

“…Lastly, in 2014, Courcet et al 115 published a study on a consanguineous family in which individuals, with severe skin dysfunction, shared a homozygous variant (c.1849G>A; p.Glu617Lys) for SASH1 115 . The major symptoms included recurrent skin cancers, loss of hair, abnormal skin pigmentation and palmoplantar keratoderma (excessive keratin production under the foot).…”

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

“…Another example represents the influence of RHBDF2 variants on EGFR signalling [145]. In the case of SASH1 mutations, wound-healing assays on control and patient-derived fibroblasts were performed to reveal alterations in pathways governing cell migration [146]. It is anticipated that functional evidence will play an increasingly important role in CRC research.…”

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

“…The SAM domain can exhibit more complex functions in these protein-protein interaction domains (15). The SAM domain mediates protein-protein interactions through homologous and heterologous oligomerization with the SAM domains of other proteins, and it can mediate Smaug protein and mRNA binding to facilitate transcriptional regulation (16,17). SASH1 is a member of a recently described family of SH3/SAM adapter molecules according to its domain structure, thus suggesting a role in signaling pathways (18).…”