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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Autores principales:	Katarzyna Gaweda-Walerych, Emilia J. Sitek, Małgorzata Borczyk, Mariusz Berdyński, Ewa Narożańska, Bogna Brockhuis, Michał Korostyński, Jarosław Sławek, Cezary Zekanowski
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	whole-genome sequencing (WGS) urokinase-type plasminogen activator (PLAU) haploinsuficiency β-site APP-cleaving enzyme 1 (BACE1) mtDNA polymerase gamma (POLG) semantic dementia atypical Alzheimer’s disease Genetics QH426-470
Acceso en línea:	https://doaj.org/article/7b78f7f8998b42bda6cc78ab736d41a2
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spelling	oai:doaj.org-article:7b78f7f8998b42bda6cc78ab736d41a22021-11-25T17:42:14ZTwo Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?10.3390/genes121118062073-4425https://doaj.org/article/7b78f7f8998b42bda6cc78ab736d41a22021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1806https://doaj.org/toc/2073-4425We 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.Katarzyna Gaweda-WalerychEmilia J. SitekMałgorzata BorczykMariusz BerdyńskiEwa NarożańskaBogna BrockhuisMichał KorostyńskiJarosław SławekCezary ZekanowskiMDPI AGarticlewhole-genome sequencing (WGS)urokinase-type plasminogen activator (PLAU) haploinsuficiencyβ-site APP-cleaving enzyme 1 (BACE1)mtDNA polymerase gamma (POLG)semantic dementiaatypical Alzheimer’s diseaseGeneticsQH426-470ENGenes, Vol 12, Iss 1806, p 1806 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	whole-genome sequencing (WGS) urokinase-type plasminogen activator (PLAU) haploinsuficiency β-site APP-cleaving enzyme 1 (BACE1) mtDNA polymerase gamma (POLG) semantic dementia atypical Alzheimer’s disease Genetics QH426-470
spellingShingle	whole-genome sequencing (WGS) urokinase-type plasminogen activator (PLAU) haploinsuficiency β-site APP-cleaving enzyme 1 (BACE1) mtDNA polymerase gamma (POLG) semantic dementia atypical Alzheimer’s disease Genetics QH426-470 Katarzyna Gaweda-Walerych Emilia J. Sitek Małgorzata Borczyk Mariusz Berdyński Ewa Narożańska Bogna Brockhuis Michał Korostyński Jarosław Sławek Cezary Zekanowski Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
description	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.
format	article
author	Katarzyna Gaweda-Walerych Emilia J. Sitek Małgorzata Borczyk Mariusz Berdyński Ewa Narożańska Bogna Brockhuis Michał Korostyński Jarosław Sławek Cezary Zekanowski
author_facet	Katarzyna Gaweda-Walerych Emilia J. Sitek Małgorzata Borczyk Mariusz Berdyński Ewa Narożańska Bogna Brockhuis Michał Korostyński Jarosław Sławek Cezary Zekanowski
author_sort	Katarzyna Gaweda-Walerych
title	Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
title_short	Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
title_full	Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
title_fullStr	Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
title_full_unstemmed	Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?
title_sort	two rare variants in <i>plau</i> and <i>bace1</i> genes—do they contribute to semantic dementia clinical phenotype?
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7b78f7f8998b42bda6cc78ab736d41a2
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Two Rare Variants in <i>PLAU</i> and <i>BACE1</i> Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?

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