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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8534005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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