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 wit...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | https://eprints.nottingham.ac.uk/51095/ |
| _version_ | 1848798414602502144 |
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| author | Hartl, Daniela May, Patrick Gu, Wei Mayhaus, Manuel Pichler, Sabrina Spaniol, Christian Glaab, Enrico Bobbili, Dheeraj Reddy Antony, Paul Koegelsberger, Sandra Kurz, Alexander Grimmer, Timo Morgan, Kevin Vardarajan, Badri N. Reitz, Christiane Hardy, John Bras, Jose Guerreiro, Rita Balling, Rudi Schneider, Jochen G. Riemenschneider, Matthias |
| author_facet | Hartl, Daniela May, Patrick Gu, Wei Mayhaus, Manuel Pichler, Sabrina Spaniol, Christian Glaab, Enrico Bobbili, Dheeraj Reddy Antony, Paul Koegelsberger, Sandra Kurz, Alexander Grimmer, Timo Morgan, Kevin Vardarajan, Badri N. Reitz, Christiane Hardy, John Bras, Jose Guerreiro, Rita Balling, Rudi Schneider, Jochen G. Riemenschneider, Matthias |
| author_sort | Hartl, Daniela |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:19:24Z |
| format | Article |
| id | nottingham-51095 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:19:24Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-510952020-05-04T19:45:32Z https://eprints.nottingham.ac.uk/51095/ A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease Hartl, Daniela May, Patrick Gu, Wei Mayhaus, Manuel Pichler, Sabrina Spaniol, Christian Glaab, Enrico Bobbili, Dheeraj Reddy Antony, Paul Koegelsberger, Sandra Kurz, Alexander Grimmer, Timo Morgan, Kevin Vardarajan, Badri N. Reitz, Christiane Hardy, John Bras, Jose Guerreiro, Rita Balling, Rudi Schneider, Jochen G. Riemenschneider, Matthias 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. Nature Publishing Group 2018-07-09 Article PeerReviewed Hartl, Daniela, May, Patrick, Gu, Wei, Mayhaus, Manuel, Pichler, Sabrina, Spaniol, Christian, Glaab, Enrico, Bobbili, Dheeraj Reddy, Antony, Paul, Koegelsberger, Sandra, Kurz, Alexander, Grimmer, Timo, Morgan, Kevin, Vardarajan, Badri N., Reitz, Christiane, Hardy, John, Bras, Jose, Guerreiro, Rita, Balling, Rudi, Schneider, Jochen G. and Riemenschneider, Matthias (2018) A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Molecular Psychiatry . ISSN 1476-5578 https://www.nature.com/articles/s41380-018-0091-8 doi:10.1038/s41380-018-0091-8 doi:10.1038/s41380-018-0091-8 |
| spellingShingle | Hartl, Daniela May, Patrick Gu, Wei Mayhaus, Manuel Pichler, Sabrina Spaniol, Christian Glaab, Enrico Bobbili, Dheeraj Reddy Antony, Paul Koegelsberger, Sandra Kurz, Alexander Grimmer, Timo Morgan, Kevin Vardarajan, Badri N. Reitz, Christiane Hardy, John Bras, Jose Guerreiro, Rita Balling, Rudi Schneider, Jochen G. Riemenschneider, Matthias A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title | A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title_full | A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title_fullStr | A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title_full_unstemmed | A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title_short | A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease |
| title_sort | rare loss-of-function variant of adam17 is associated with late-onset familial alzheimer disease |
| url | https://eprints.nottingham.ac.uk/51095/ https://eprints.nottingham.ac.uk/51095/ https://eprints.nottingham.ac.uk/51095/ |