ArticleGenetics in medicine : official journal of the American College of Medical Genetics2022
Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 3 citations in OpenAlex.
- Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.Nature communications · 2024Article
- Loss of symmetric cell division of apical neural progenitors drivesmedRxiv : the preprint server for health sciences · 2024Article
- A Novel Tumor-Associated Neutrophil-Related Risk Signature Based on Single-Cell and Bulk RNA-Sequencing Analyses Predicts the Prognosis and Immune Landscape of Breast Cancer.Journal of Cancer · 2024Article
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
Abstract
purposeMore than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene.
methodsWe performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model.
resultsWe identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content.
conclusionOur findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.
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