Genetic Study of Alzheimer’s Disease in Saudi Population

• Published in: Journal of Alzheimer's disease 2019-01, Vol.67 (1), p.231-242
• Main Authors: El Bitar, Fadia, Qadi, Najeeb, Al Rajeh, Saad, Majrashi, Amna, Abdulaziz, Sara, Majrashi, Nada, Al Inizi, Maznah, Taher, Asma, Al Tassan, Nada
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Apolipoprotein E; Apolipoprotein E4; Apolipoproteins E - genetics; Case-Control Studies; Cohort Studies; Dementia disorders; Female; Gene Frequency; Gene sequencing; Genes; Genetic Predisposition to Disease; Genotype; Humans; LDL-Receptor Related Proteins - genetics; Male; Membrane Transport Proteins - genetics; Middle Aged; Molecular Structure; Mutation; Mutation, Missense - genetics; Neural coding; Patients; Pedigree; Point Mutation - genetics; Population genetics; Presenilin-1 - genetics; Presenilin-2 - genetics; Protein structure; Proteins; Saudi Arabia; Structural analysis; Young Adult
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-180415

Background: Alzheimer’s disease (AD) is a chronic neurological disorder associated with mental decline and dementia. Several studies focused on investigating the molecular basis of the disease that led to the identification of several causative genes and risk associated alleles. Replication of these studies and findings from different populations is very important. Objective: Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia. Methods: Comprehensive screening for point mutations was carried out by direct sequencing of coding regions in the three known AD causative genes: PSEN1, PSEN2, APP, as well as the AD associated gene SORL1. All patients were also genotyped for APOE alleles. In silico 3D protein structure analysis was performed for two novel SORL1 variants. Results: We identified a total of eight potential pathogenic missense variants in all studied genes. Five of these variants were not previously reported including four in SORL1 (p.Val297Met, p.Arg1084Cys, p.Asp1100Asn, and p.Pro1213Ser) and one in APP (p.Glu380Lys). The frequency of APOE-ɛ4 allele was 21.37% of total investigated cases. In silico 3D protein structure analysis of two SORL1 novel missense variants (p.Pro1213Ser and p.Arg1084Cys) suggested that these variants may affect the folding of the proteins and disturb their structure. Conclusions: Our comprehensive analysis of the open reading frame of the known genes have identified potential pathogenic rare variants in 18/117 cases. We found that point mutations in AD main genes (PSEN1, PSEN2, and APP) were underrepresented in our cohort of patients. Our results confirm involvement of SORL1 in familial and sporadic AD cases.