Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma

Genet Med. 2022 Jan;24(1):157-169. doi: 10.1016/j.gim.2021.09.003. Epub 2021 Nov 30.


Purpose: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene.

Methods: We 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.

Results: We 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.

Conclusion: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.

Keywords: DENND5A; Melanoma; Pigmentation; SNX1; Susceptibility gene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Exome Sequencing
  • Genetic Predisposition to Disease
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Melanoma* / genetics
  • Melanosomes
  • Monophenol Monooxygenase / metabolism
  • Skin Neoplasms* / genetics
  • Sorting Nexins
  • Zebrafish / genetics


  • DENND5A protein, human
  • Guanine Nucleotide Exchange Factors
  • SNX1 protein, human
  • Sorting Nexins
  • Monophenol Monooxygenase