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Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 50 million people worldwide in 2020 and this number will triple to 152 million by 2050. Much of the increase will be in developing countries like Colombia. In familial forms, highly penetrant mutations have...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337667/ https://www.ncbi.nlm.nih.gov/pubmed/35905044 http://dx.doi.org/10.1371/journal.pone.0269955 |
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author | Tejada Moreno, Johanna Alexandra Villegas Lanau, Andrés Madrigal Zapata, Lucia Baena Pineda, Ana Yulied Velez Hernandez, Juan Campo Nieto, Omer Soto Ospina, Alejandro Araque Marín, Pedronel Rishishwar, Lavanya Norris, Emily T. Chande, Aroon T. Jordan, I. King Bedoya Berrio, Gabriel |
author_facet | Tejada Moreno, Johanna Alexandra Villegas Lanau, Andrés Madrigal Zapata, Lucia Baena Pineda, Ana Yulied Velez Hernandez, Juan Campo Nieto, Omer Soto Ospina, Alejandro Araque Marín, Pedronel Rishishwar, Lavanya Norris, Emily T. Chande, Aroon T. Jordan, I. King Bedoya Berrio, Gabriel |
author_sort | Tejada Moreno, Johanna Alexandra |
collection | PubMed |
description | Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 50 million people worldwide in 2020 and this number will triple to 152 million by 2050. Much of the increase will be in developing countries like Colombia. In familial forms, highly penetrant mutations have been identified in three genes, APP, PSEN1, and PSEN2, supporting a role for amyloid-β peptide. In sporadic forms, more than 30 risk genes involved in the lipid metabolism, the immune system, and synaptic functioning mechanisms. We used whole-exome sequencing (WES) to evaluate a family of 97 members, spanning three generations, with a familiar AD, and without mutations in APP, PSEN1, or PSEN2. We sequenced two affected and one unaffected member with the aim of identifying genetic variants that could explain the presence of the disease in the family and the candidate variants were validated in eleven members. We also built a structural model to try to determine the effect on protein function. WES analysis identified two rare variants in SORL1 and MTHFD1L genes segregating in the family with other potential risk variants in APOE, ABCA7, and CHAT, suggesting an oligogenic inheritance. Additionally, the structural 3D models of SORL1 and MTHFD1L variants shows that these variants produce polarity changes that favor hydrophobic interactions, resulting in local structural changes that could affect the protein function and may contribute to the development of the disease in this family. |
format | Online Article Text |
id | pubmed-9337667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-93376672022-07-30 Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family Tejada Moreno, Johanna Alexandra Villegas Lanau, Andrés Madrigal Zapata, Lucia Baena Pineda, Ana Yulied Velez Hernandez, Juan Campo Nieto, Omer Soto Ospina, Alejandro Araque Marín, Pedronel Rishishwar, Lavanya Norris, Emily T. Chande, Aroon T. Jordan, I. King Bedoya Berrio, Gabriel PLoS One Research Article Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 50 million people worldwide in 2020 and this number will triple to 152 million by 2050. Much of the increase will be in developing countries like Colombia. In familial forms, highly penetrant mutations have been identified in three genes, APP, PSEN1, and PSEN2, supporting a role for amyloid-β peptide. In sporadic forms, more than 30 risk genes involved in the lipid metabolism, the immune system, and synaptic functioning mechanisms. We used whole-exome sequencing (WES) to evaluate a family of 97 members, spanning three generations, with a familiar AD, and without mutations in APP, PSEN1, or PSEN2. We sequenced two affected and one unaffected member with the aim of identifying genetic variants that could explain the presence of the disease in the family and the candidate variants were validated in eleven members. We also built a structural model to try to determine the effect on protein function. WES analysis identified two rare variants in SORL1 and MTHFD1L genes segregating in the family with other potential risk variants in APOE, ABCA7, and CHAT, suggesting an oligogenic inheritance. Additionally, the structural 3D models of SORL1 and MTHFD1L variants shows that these variants produce polarity changes that favor hydrophobic interactions, resulting in local structural changes that could affect the protein function and may contribute to the development of the disease in this family. Public Library of Science 2022-07-29 /pmc/articles/PMC9337667/ /pubmed/35905044 http://dx.doi.org/10.1371/journal.pone.0269955 Text en © 2022 Tejada Moreno et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Tejada Moreno, Johanna Alexandra Villegas Lanau, Andrés Madrigal Zapata, Lucia Baena Pineda, Ana Yulied Velez Hernandez, Juan Campo Nieto, Omer Soto Ospina, Alejandro Araque Marín, Pedronel Rishishwar, Lavanya Norris, Emily T. Chande, Aroon T. Jordan, I. King Bedoya Berrio, Gabriel Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title | Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title_full | Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title_fullStr | Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title_full_unstemmed | Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title_short | Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer’s disease in a multigenerational Colombian Family |
title_sort | mutations in sorl1 and mthfdl1 possibly contribute to the development of alzheimer’s disease in a multigenerational colombian family |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337667/ https://www.ncbi.nlm.nih.gov/pubmed/35905044 http://dx.doi.org/10.1371/journal.pone.0269955 |
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