Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
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 sign...
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| Main Authors: | , , , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
MDPI AG
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/7b78f7f8998b42bda6cc78ab736d41a2 |
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| Summary: | 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 β-site APP-cleaving enzyme 1 (BACE1)—along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced <i>PLAU</i> and elevated <i>BACE1</i> mRNA and protein levels compared to control fibroblasts. Successful rescue of <i>PLAU</i> mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the <i>PLAU</i> variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the <i>PLAU</i> and <i>BACE1</i> genes should be considered in future studies on early-onset dementias. |
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