1. A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease
- Author
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Hartl, D, May, P, Gu, W, Mayhaus, M, Pichler, S, Spaniol, C, Glaab, E, Bobbili, DR, 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, Sassi, C, Gibbs, JR, Hernandez, D, Brookes, KJ, Guetta-Baranes, T, Francis, PT, Lupton, MK, Brown, K, Powell, J, and Singleton, A
- Subjects
0301 basic medicine ,Nonsynonymous substitution ,Male ,Molecular biology ,Genome-wide association study ,Biology ,ADAM17 Protein ,Article ,Transcriptome ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Amyloid beta-Protein Precursor ,0302 clinical medicine ,Alzheimer Disease ,Loss of Function Mutation ,Germany ,Exome Sequencing ,Genetics ,Humans ,Genetic Predisposition to Disease ,Gene ,Genotyping ,Loss function ,Genetic association ,Aged ,Middle Aged ,3. Good health ,ddc ,Psychiatry and Mental health ,030104 developmental biology ,Case-Control Studies ,Mutation ,Female ,Amyloid Precursor Protein Secretases ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Neuroscience - 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.
- Published
- 2017