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Novel loss-of-funct...
Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
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- Yang, Muyi (author)
- Karolinska Institutet
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- Johnsson, Per (author)
- Karolinska Institutet
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- Bräutigam, Lars (author)
- Karolinska Institutet
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- Yang, Xiaohong R. (author)
- NCI, Div Canc Epidemiol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
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- Thrane, Kim (author)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab
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- Gao, Jiwei (author)
- Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
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- Tobin, Nicholas P. (author)
- Karolinska Institutet
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- Zhou, Yitian (author)
- Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, Stockholm, Sweden.
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- Yu, Rong (author)
- Karolinska Institutet
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- Nagy, Noemi (author)
- Karolinska Institutet
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- Engström, Pär G. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, SciLifeLab, Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden.
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- Tuominen, Rainer (author)
- Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
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- Eriksson, Hanna (author)
- Karolinska Institutet
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- Lundeberg, Joakim (author)
- KTH,Science for Life Laboratory, SciLifeLab,Genteknologi
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- Tucker, Margaret A. (author)
- NCI, Div Canc Epidemiol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
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- Goldstein, Alisa M. (author)
- NCI, Div Canc Epidemiol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
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- Egyhazi-Brage, Suzanne (author)
- Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
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- Zhao, Jian (author)
- Karolinska Institutet
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- Cao, Yihai (author)
- Karolinska Institutet
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- Höiom, Veronica (author)
- Karolinska Institutet
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Karolinska Institutet NCI, Div Canc Epidemiol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA (creator_code:org_t)
- Elsevier BV, 2022
- 2022
- English.
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:1, s. 157-169
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- DENND5A
- Melanoma
- Pigmentation
- SNX1
- Susceptibility gene
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Yang, Muyi
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Johnsson, Per
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Bräutigam, Lars
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Yang, Xiaohong R ...
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Thrane, Kim
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Gao, Jiwei
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show more...
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Tobin, Nicholas ...
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Zhou, Yitian
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Yu, Rong
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Nagy, Noemi
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Engström, Pär G.
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Tuominen, Rainer
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Eriksson, Hanna
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Lundeberg, Joaki ...
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Tucker, Margaret ...
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Goldstein, Alisa ...
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Egyhazi-Brage, S ...
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Zhao, Jian
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Cao, Yihai
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Höiom, Veronica
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Genetics in Medi ...
- By the university
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Royal Institute of Technology
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Stockholm University
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Karolinska Institutet