Two Rare Variants in PLAU and BACE1 Genes-Do They Contribute to Semantic Dementia Clinical Phenotype?
Genes (Basel)
; 12(11)2021 11 17.
Article
em En
| MEDLINE
| ID: mdl-34828412
ABSTRACT
We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in ß-site APP-cleaving enzyme 1 (BACE1)-along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.
Palavras-chave
atypical Alzheimer's disease; magnetic resonance imaging (MRI); mtDNA polymerase gamma (POLG); primary skin fibroblasts; semantic dementia; single-photon emission computed tomography (SPECT); urokinase-type plasminogen activator (PLAU) haploinsuficiency; whole-genome sequencing (WGS); ß-site APP-cleaving enzyme 1 (BACE1)
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Aspártico Endopeptidases
/
Penetrância
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Secretases da Proteína Precursora do Amiloide
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Demência Frontotemporal
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Proteínas de Membrana
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Genes (Basel)
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Polônia