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

Daniela Hartl,Enrico Glaab,Rita Guerreiro,Paul Antony,Alexander Kurz,Rudi Balling,Sabrina Pichler,Dheeraj Reddy Bobbili,Christian Spaniol,Christiane Reitz,Jochen G Schneider,Badri N Vardarajan,Timo Grimmer,Wei Gu,Manuel Mayhaus,Kevin Morgan,Sandra Koegelsberger,John Hardy,Patrick May,José Brás ,Matthias Riemenschneider

doi:10.1038/s41380-018-0091-8

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.

Highlights

Members of AESG are listed below AcknowledgementsThese authors are contributed: Daniela Hartl, Patrick May, Wei GuElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Nottingham, Nottingham, UK 6 Taub Institute for Research on Alzheimer’s Disease and the AgingBrain, College of Physicians and Surgeons, Columbia University, The central theory on Alzheimer disease (AD) pathogenesis is the amyloid cascade hypothesis with amyloid ß peptides (Aß), formed from the ß-amyloid precursor protein (APP) as etiologic agent [1]
We identified an single rare nonsynonymous variant (SNV) of ADAM17 co-segregating with the disease in a family with an autosomal-dominant pattern of inheritance of late-onset AD
The presence of the heterozygous ADAM17 variant in the two affected family members was confirmed by Sanger sequencing and identified in two additional affected family members (121, 124, Fig. 1) that have not been analyzed by whole-genome sequencing (WGS)

Summary

Introduction

Members of AESG are listed below Acknowledgements. Nottingham, Nottingham, UK 6 Taub Institute for Research on Alzheimer’s Disease and the Aging. College of Physicians and Surgeons, Columbia University, The central theory on Alzheimer disease (AD) pathogenesis is the amyloid cascade hypothesis with amyloid ß peptides (Aß), formed from the ß-amyloid precursor protein (APP) as etiologic agent [1]. The importance of APP metabolism was confirmed by genome-wide association studies (GWAS) and reports of rare gene variants in patients with familial. 10 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. 12 Department of Medical Sciences, Institute of BiomedicineiBiMED, University of Aveiro, Aveiro, Portugal. There is still a large proportion of missing heritability that might be explained by rare but functionally important variants

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Results

Conclusion