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Mol Psychiatry. 2017 Aug;22(8):1119-1125. doi: 10.1038/mp.2016.226. Epub 2016 Dec 13.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

Author information

1
Inserm, U1079, faculté de médecine, Rouen University, IRIB, Normandy University, Rouen, France.
2
Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.
3
CNR-MAJ, Rouen University Hospital, Rouen, France.
4
Department of Genetics, Rouen University Hospital, Rouen, France.
5
Department of Neurology, Rouen University Hospital, Rouen, France.
6
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
7
Inserm, U1167, Lille, France.
8
Institut Pasteur de Lille, Lille, France.
9
Université Lille-Nord de France, Lille, France.
10
Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
11
Fondation Jean Dausset, Centre d'études du Polymorphisme Humain, Paris, France.
12
McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
13
Inserm, UMR 1087, l'institut du thorax, CHU Nantes, Nantes, France.
14
CNRS, UMR 6291, Université de Nantes, Nantes, France.
15
INSERM, U1219, Bordeaux, France.
16
Université de Bordeaux, Bordeaux, France.
17
Institute of Pathology and Neuropathology, Kepler University Hospital, Linz, Austria.
18
Department of Neurology, Alexandrovska University Hospital, Medical University-Sofia, Sofia, Bulgaria.
19
Institute of Neurology, Medical University Vienna, Vienna, Austria.
20
Sorbonne Universités, Inserm, CNRS, UPMC Univ Paris 06, UMR S 1127, Paris, France.
21
CNR-MAJ, IMMA, département des maladies du système nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
22
Centre Mémoire de Ressources et de Recherche de Lorraine, CHRU Nancy Service de Gériatrie, Hôpital de Brabois, Vandoeuvre les Nancy, France.
23
Laboratoire INTERPSY, EA 4432, Groupe de recherche sur les Communications (GRC), Université de Lorraine, Psychologie, Nancy, France.
24
CNR-MAJ Inserm U1171, Univ Lille, CHU, Lille, France.
25
Inserm, UMR1078, CHU Brest, Université Bretagne Occidentale, Brest, France.
26
Department of Neurophysiology, Rouen University Hospital, Rouen, France.
27
Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.

Abstract

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

PMID:
27956742
DOI:
10.1038/mp.2016.226
[Indexed for MEDLINE]

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