PUBLICATION
Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
- Authors
- Yang, M., Johnsson, P., Bräutigam, L., Yang, X.R., Thrane, K., Gao, J., Tobin, N.P., Zhou, Y., Yu, R., Nagy, N., Engström, P.G., Tuominen, R., Eriksson, H., Lundeberg, J., Tucker, M.A., Goldstein, A.M., Egyhazi-Brage, S., Zhao, J., Cao, Y., Höiom, V.
- ID
- ZDB-PUB-211216-12
- Date
- 2021
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 24(1): 157-169 (Journal)
- Registered Authors
- Keywords
- DENND5A, Melanoma, Pigmentation, SNX1, Susceptibility gene
- 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
- PubMed
- 34906508 Full text @ Genet. Med.
Citation
Yang, M., Johnsson, P., Bräutigam, L., Yang, X.R., Thrane, K., Gao, J., Tobin, N.P., Zhou, Y., Yu, R., Nagy, N., Engström, P.G., Tuominen, R., Eriksson, H., Lundeberg, J., Tucker, M.A., Goldstein, A.M., Egyhazi-Brage, S., Zhao, J., Cao, Y., Höiom, V. (2021) Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma. Genetics in medicine : official journal of the American College of Medical Genetics. 24(1):157-169.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping