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

ABSTRACT: 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.

• Autores: Tejada Moreno, Johanna Alexandra; Villegas Lanau, Carlos Andrés; Madrigal Zapata, Lucia del Socorro; Baena Pineda, Ana Yulied; Vélez Hernández, Juan Esteban; Campo Nieto, Omer; Soto Ospina, Johnny Alejandro; Bedoya Berrío, Gabriel de Jesús; Rishishwar, Lavanya; Norris, Emily T; Chande, Aroon T; Jordan, I King; Araque Marín, Pedronel
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2022
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/41082
• Acceso en línea: https://hdl.handle.net/10495/41082
• Palabra clave: Alzheimer Disease; Enfermedad de Alzheimer; Amyloid beta-Protein Precursor; Precursor de Proteína beta-Amiloide; Exome Sequencing; Secuenciación del Exoma; Genetic Predisposition to Disease; Predisposición Genética a la Enfermedad; LDL-Receptor Related Proteins; Proteínas Relacionadas con Receptor de LDL; Membrane Transport Proteins; Proteínas de Transporte de Membrana; Mutation; Mutación; Presenilin-1; Presenilina-1; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D016564; https://id.nlm.nih.gov/mesh/D000073359; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D026502; https://id.nlm.nih.gov/mesh/D026901; https://id.nlm.nih.gov/mesh/D009154; https://id.nlm.nih.gov/mesh/D053764
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/