ACE-Dependent Alzheimer’s Disease: Blood ACE Phenotyping of the Most Prevalent and Damaging ACE Missense Mutation—Y215C (rs3730025)

Buianova, A.A.; Adzhubei, I.A.; Kryukova, O.V.; Kost, O.A.; Mironenko, I.V.; Kozuch, A.S.; Ilyina, G.A.; Kuznetsova, A.A.; Repinskaia, Z.A.; Churov, A.V.; Dudek, S.M.; Rebrikov, D.V.; Danilov, S.M.

Авторы: Buianova A.A., Adzhubei I.A., Kryukova O.V., Kost O.A., Mironenko I.V., Kozuch A.S., Ilyina G.A., Kuznetsova A.A., Repinskaia Z.A., Churov A.V., Dudek S.M., Rebrikov D.V., Danilov S.M.
Журнал: BIOMEDICINES
Том: 14
Номер: 2
Год издания: 2026
Первая страница: 1
Последняя страница: 27
Номер статьи: 275
DOI: 10.3390/biomedicines14020275
Аннотация: Background: The ACE Y215C mutation is a common, functionally damaging missensevariant (~1.5% allele frequency) associated with reduced plasma ACE levels and increasedAlzheimer’s disease (AD) risk. In CHO and HEK cell models, this mutation caused a~3–6-fold decrease in ACE surface expression, soluble ACE levels, and ACE enzymaticactivity compared to those of wild-type ACE. Methods: Circulating ACE levels and activitywere measured in EDTA plasma obtained from 84 carriers of the ACE Y215C mutationusing a set of mAbs to the ACE. The mAbs 5B3/1G12 binding ratio was revealed as asensitive marker for the circulating Y215C ACE mutant. Whole-exome and whole-genomesequencing (WES/WGS) were performed to identify genetic variants potentially modifyingcirculating ACE levels. In parallel, published sequencing and proteomic data from35,559 Icelanders participants were analyzed to identify genes influencing ACE shedding.Sequence comparison was performed between carriers with elevated and reduced ACEconcentrations to identify the potential protective variants that may compensate for decreasedACE levels due to the Y215C mutation itself. Results: Most carriers of the Y215CACE mutation demonstrated significantly decreased ACE levels (median is 62% of controlACE levels). However, substantial inter-individual variability was observed in plasma ACEactivity among carriers. Comparative sequencing analysis revealed 9648 variants unique toindividuals with elevated ACE, mapping to 5779 protein-coding genes and enriched forpathways related to intracellular and transmembrane transport. Conclusions: The presenceof the damaging ACE mutation Y215C does not invariably result in low plasma ACE or,likely, elevated AD risk. Therefore, combined blood ACE phenotyping and whole-exomesequencing are recommended to more accurately assess ACE-related AD susceptibility inmutation carriers.
Добавил в систему: Крюкова Ольга Владимировна

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ACE-Dependent Alzheimer’s Disease: Blood ACE Phenotyping of the Most Prevalent and Damaging ACE Missense Mutation—Y215C (rs3730025)статья Исследовательская статья

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