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A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family

Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer’s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of di...

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Autores principales: Bagyinszky, Eva, Ch’ng, Gaik-Siew, Chan, Mei-Yan, An, Seong Soo A., Kim, SangYun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534005/
https://www.ncbi.nlm.nih.gov/pubmed/34679393
http://dx.doi.org/10.3390/brainsci11101328
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author Bagyinszky, Eva
Ch’ng, Gaik-Siew
Chan, Mei-Yan
An, Seong Soo A.
Kim, SangYun
author_facet Bagyinszky, Eva
Ch’ng, Gaik-Siew
Chan, Mei-Yan
An, Seong Soo A.
Kim, SangYun
author_sort Bagyinszky, Eva
collection PubMed
description Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer’s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of disease. This is the second report of PSEN1 Val96Phe mutation among EOAD patients in Asia and in the world. Patients presented symptomatic changes in their behaviors and personality, such as apathy and withdrawal in their 40s. Previous cellular studies with COS1 cell lines revealed the mutation increased the amyloid-β42 (Aβ42) productions. In the present study, whole-exome sequencing was performed on the two siblings with EOAD, and they were analyzed against the virtual panel of 100 genes from various neurodegenerative diseases. In silico modeling was also performed on PSEN1 Val96Phe mutation. This mutation was located on the first transmembrane helix of PSEN1 protein, resulting significant intramolecular stresses in the helices. This helical domain would play a significant role in γ-secretase cleavage for the increased Aβ42 productions. Several other adjacent mutations were reported in this helical domain, including Ile83Thr or Val89Leu. Our study suggested that perturbations in TMI-HLI-TMII regions could also be associated with C-terminal fragment accumulation of APP and enhanced amyloid productions.
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spelling pubmed-85340052021-10-23 A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family Bagyinszky, Eva Ch’ng, Gaik-Siew Chan, Mei-Yan An, Seong Soo A. Kim, SangYun Brain Sci Case Report Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer’s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of disease. This is the second report of PSEN1 Val96Phe mutation among EOAD patients in Asia and in the world. Patients presented symptomatic changes in their behaviors and personality, such as apathy and withdrawal in their 40s. Previous cellular studies with COS1 cell lines revealed the mutation increased the amyloid-β42 (Aβ42) productions. In the present study, whole-exome sequencing was performed on the two siblings with EOAD, and they were analyzed against the virtual panel of 100 genes from various neurodegenerative diseases. In silico modeling was also performed on PSEN1 Val96Phe mutation. This mutation was located on the first transmembrane helix of PSEN1 protein, resulting significant intramolecular stresses in the helices. This helical domain would play a significant role in γ-secretase cleavage for the increased Aβ42 productions. Several other adjacent mutations were reported in this helical domain, including Ile83Thr or Val89Leu. Our study suggested that perturbations in TMI-HLI-TMII regions could also be associated with C-terminal fragment accumulation of APP and enhanced amyloid productions. MDPI 2021-10-08 /pmc/articles/PMC8534005/ /pubmed/34679393 http://dx.doi.org/10.3390/brainsci11101328 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Bagyinszky, Eva
Ch’ng, Gaik-Siew
Chan, Mei-Yan
An, Seong Soo A.
Kim, SangYun
A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title_full A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title_fullStr A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title_full_unstemmed A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title_short A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
title_sort pathogenic presenilin-1 val96phe mutation from a malaysian family
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534005/
https://www.ncbi.nlm.nih.gov/pubmed/34679393
http://dx.doi.org/10.3390/brainsci11101328
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