Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America.

Autor: Takada LT; Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil., Aláez-Verson C; Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, México., Burgute BD; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA., Nitrini R; Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil., Sosa AL; Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico, Mexico., Castilhos RM; Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Chaves MF; Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Department of Internal Medicine, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil., Longoria EM; Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico, Mexico., Carrillo-Sánchez K; Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, México., Brucki SMD; Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil., Flores-Lagunes LL; Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, México., Molina C; Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, México., Olivares MJ; Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, México., Ziegemeier E; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA., Petranek J; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA., Goate AM; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Cruchaga C; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA., Renton AE; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fernández MV; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA., Day GS; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA., McDade E; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA., Bateman RJ; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA., Karch CM; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA., Llibre-Guerra JJ; Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. jllibre-guerra@wustl.edu.
Jazyk: angličtina
Zdroj: Alzheimer's research & therapy [Alzheimers Res Ther] 2022 Aug 05; Vol. 14 (1), pp. 108. Date of Electronic Publication: 2022 Aug 05.
DOI: 10.1186/s13195-022-01052-1
Abstrakt: Background: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.
Methods: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios.
Results: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation.
Conclusions: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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