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A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.

TitleA rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsHartl D, May P, Gu W, Mayhaus M, Pichler S, Spaniol C, Glaab E, Bobbili DReddy, Antony P, Koegelsberger S, Kurz A, Grimmer T, Morgan K, Vardarajan BN, Reitz C, Hardy J, Bras J, Guerreiro R, Balling R, Schneider JG, Riemenschneider M
Corporate AuthorsAESG
JournalMol Psychiatry
Date Published2020 03
KeywordsADAM17 Protein, Aged, Alzheimer Disease, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germany, Humans, Loss of Function Mutation, Male, Middle Aged, Mutation, Whole Exome Sequencing

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.

Pubmed Link
Alternate JournalMol Psychiatry
PubMed ID29988083
PubMed Central IDPMC7042727
Grant List / WT_ / Wellcome Trust / United Kingdom
R01 AG037212 / AG / NIA NIH HHS / United States
RF1 AG054023 / AG / NIA NIH HHS / United States
Z01 AG000950 / ImNIH / Intramural NIH HHS / United States

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