Mutations in SORL1 and MTHFDL1 possibly contribute to the development of Alzheimer's disease in a multigenerational Colombian Family.

Autor: Tejada Moreno JA; Molecular Genetics Research Group, University of Antioquia, Medellin, Colombia., Villegas Lanau A; Neuroscience Research Group, University of Antioquia, Medellin, Colombia., Madrigal Zapata L; Neuroscience Research Group, University of Antioquia, Medellin, Colombia., Baena Pineda AY; Neuroscience Research Group, University of Antioquia, Medellin, Colombia., Velez Hernandez J; Neuroscience Research Group, University of Antioquia, Medellin, Colombia., Campo Nieto O; Molecular Genetics Research Group, University of Antioquia, Medellin, Colombia., Soto Ospina A; Molecular Genetics Research Group, University of Antioquia, Medellin, Colombia., Araque Marín P; Research and Innovation Group in Chemical Formulations, EIA University, Medellin, Colombia., Rishishwar L; IHRC-Georgia Tech Applied Bioinformatics Laboratory, Atlanta, Georgia, United States of America.; PanAmerican Bioinformatics Institute, Cali, Valle del Cauca, Colombia., Norris ET; IHRC-Georgia Tech Applied Bioinformatics Laboratory, Atlanta, Georgia, United States of America.; PanAmerican Bioinformatics Institute, Cali, Valle del Cauca, Colombia.; School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America., Chande AT; IHRC-Georgia Tech Applied Bioinformatics Laboratory, Atlanta, Georgia, United States of America.; PanAmerican Bioinformatics Institute, Cali, Valle del Cauca, Colombia.; School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America., Jordan IK; IHRC-Georgia Tech Applied Bioinformatics Laboratory, Atlanta, Georgia, United States of America.; PanAmerican Bioinformatics Institute, Cali, Valle del Cauca, Colombia.; School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America., Bedoya Berrio G; Molecular Genetics Research Group, University of Antioquia, Medellin, Colombia.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2022 Jul 29; Vol. 17 (7), pp. e0269955. Date of Electronic Publication: 2022 Jul 29 (Print Publication: 2022).
DOI: 10.1371/journal.pone.0269955
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist
Databáze: MEDLINE
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