116 research outputs found
Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease
The Effect of Foreign Affiliate Employment on Wages, Employment, and the Wage Share in Austria
A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease
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
Plant α‐glucan phosphatases SEX4 and LSF2 display different affinity for amylopectin and amylose
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