17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.
Mol Psychiatry
; 22(8): 1119-1125, 2017 08.
Article
en En
| MEDLINE
| ID: mdl-27956742
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-ß 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Cromosomas Humanos Par 17
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Demencia
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Enfermedad de Alzheimer
Tipo de estudio:
Etiology_studies
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Observational_studies
Idioma:
En
Revista:
Mol Psychiatry
Asunto de la revista:
BIOLOGIA MOLECULAR
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PSIQUIATRIA
Año:
2017
Tipo del documento:
Article