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A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques
- Source :
- Moreno, F; Rabinovici, GD; Karydas, A; Miller, Z; Hsu, SC; Legati, A; et al.(2015). A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques. ACTA NEUROPATHOLOGICA COMMUNICATIONS, 3, 19. doi: 10.1186/s40478-015-0190-6. UCSF: Retrieved from: http://www.escholarship.org/uc/item/2693t5g7, Acta neuropathologica communications, vol 3, iss 1, Acta Neuropathologica Communications
- Publication Year :
- 2015
- Publisher :
- eScholarship, University of California, 2015.
-
Abstract
- Introduction Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. Results We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. Conclusions TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Aging
TDP-43
Plaque, Amyloid
Neurodegenerative
Alzheimer's Disease
Inclusion bodies
C9orf72
2.1 Biological and endogenous factors
Aetiology
Alzheimer's Disease Related Dementias (ADRD)
TARDBP
Plaque
Inclusion Bodies
Autosomal dominant trait
Brain
Frontotemporal lobar degeneration
Middle Aged
3. Good health
Pedigree
DNA-Binding Proteins
Frontotemporal Dementia (FTD)
Neurological
Female
Tauopathy
Psychology
Frontotemporal dementia
Amyloid
Clinical Sciences
Pathology and Forensic Medicine
Cellular and Molecular Neuroscience
Rare Diseases
Parkinsonian Disorders
mental disorders
Genetics
Acquired Cognitive Impairment
medicine
Dementia
Humans
Motor neuron disease
Motor Neuron Disease
Aged
Research
Siblings
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
medicine.disease
Brain Disorders
Postmortem
Mutation
Neurology (clinical)
Biochemistry and Cell Biology
Frontotemporal Lobar Degeneration
Neuroscience
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Moreno, F; Rabinovici, GD; Karydas, A; Miller, Z; Hsu, SC; Legati, A; et al.(2015). A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques. ACTA NEUROPATHOLOGICA COMMUNICATIONS, 3, 19. doi: 10.1186/s40478-015-0190-6. UCSF: Retrieved from: http://www.escholarship.org/uc/item/2693t5g7, Acta neuropathologica communications, vol 3, iss 1, Acta Neuropathologica Communications
- Accession number :
- edsair.doi.dedup.....331fe823d837bc6bdeffd7c6a3daa851