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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity

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Autor(es):
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Chen, Che-Hong [1] ; Ferreira, Julio C. B. [2, 1] ; Joshi, Amit U. [1] ; Stevens, Matthew C. [1] ; Li, Sin-Jin [1, 3] ; Hsu, Jade H. -M. [1, 4] ; Maclean, Rory [1] ; Ferreira, Nikolas D. [2] ; Cervantes, Pilar R. [5] ; Martinez, Diana D. [5] ; Barrientos, Fernando L. [5] ; Quintanares, Gibran H. R. [5] ; Mochly-Rosen, Daria [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 - USA
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil
[3] Natl Taiwan Univ, Dept Anim Sci & Technol, Taipei - Taiwan
[4] Natl Yang Ming Univ, Dept Biotechnol & Lab Sci Med, Taipei - Taiwan
[5] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Translat Med & Innovat Unit, Dept Infect Dis, Mexico City, DF - Mexico
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: EBIOMEDICINE; v. 55, MAY 2020.
Citações Web of Science: 0
Resumo

Background: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2{*}2 (E504K) that leads to accumulation of toxic reactive aldehydes. Methods: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. Findings: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. Interpretation: Since similar to 80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new `precision medicine' for carriers of these inactive ALDH2. (C) 2020 The Author(s). Published by Elsevier B.V. (AU)

Processo FAPESP: 18/18627-3 - Mecanismos envolvidos na mitofagia induzida pelo exercício físico: uma nova estratégia no processo de descoberta de fármacos
Beneficiário:Julio Cesar Batista Ferreira
Linha de fomento: Bolsas no Exterior - Pesquisa