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

Abstract

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.

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

“…It is possible that cryptic relatedness in the sample may have exaggerated some of our results; however, among the highlighted findings, the largest pairwise IBD score of 0.11 (indicating an association slightly more distant than first-cousins) was observed for 1 pair of NOTCH3 mutation carriers. Our scheme for selecting genes previously associated with AD, AD-related traits, or other dementias omitted important loci that were reported after we completed most of our analyses (eg, ADAM17 63 ), ascertained through a connection to a nondementing illness (eg, TBK1 64 ), or do not have variants linked to late-onset AD (eg, TYROBP 65 ). In addition, because we were unable to validate all rare variants reported in this study owing, in part, to availability of specimens containing these variants, some of the highlighted associations may be false-positives due to variant calling errors.…”

Immune Signaling in Neurodegeneration

“…This cleavage site on TREM2 is also the site of an AD risk SNP in the Han Chinese population (Jiang et al, 2014). Alpha-secretase cleavage is also a critical part of the amyloid processing pathway of APP, and both rare and common variants in ADAM10 and ADAM17 have been found to increase AD risk (Hartl et al, 2018;Kim et al, 2009;Kunkle et al, 2019). The TREM2 H157Y variants is thought to result in loss of function of TREM2 via increased cleavage of TREM2 into sTREM2 (Schlepckow et al, 2017;Thornton et al, 2017).…”

Tuning of Glutamate, But Not GABA, Release by an Intrasynaptic Vesicle APP Domain Whose Function Can Be Modulated by β- or α-Secretase Cleavage

“…Mutations in APP and in genes that regulate APP processing, such as the ␥-secretase components PSEN1/PSEN2 and BRI2/ITM2B, cause FAD and the AD-like familial British dementia and familial Danish dementia (Matsuda et al, 2005(Matsuda et al, , 2008(Matsuda et al, , 2011aGiliberto et al, 2009;Garringer et al, 2010;Tamayev et al, 2010aTamayev et al, ,b, 2011Tamayev et al, , 2012bDe Strooper and Voet, 2012). Increased BACE1 expression/activity and BACE1 gene polymorphisms are associated with SAD (Jo et al, 2008;Hampel and Shen, 2009;Cheng et al, 2014;Long et al, 2014); loss-of-function mutation in genes coding for proteins with ␣-secretase activity are associated with SAD (Suh et al, 2013;Hartl et al, 2018). This genetic evidence, coupled to the identification of A␤ as the main component of senile plaques, provides the foundation for the "amyloid hypothesis," which states, briefly, that A␤ is the toxic metabolite responsible for neurodegeneration in AD.…”