Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.
Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.
J Alzheimers Dis. 2019;67(1):231-242. doi: 10.3233/JAD-180415.
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.
Molecular assessment of a cohort of 117 familial and sporadic AD cases from Saudi Arabia.
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.
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.
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.
阿尔茨海默病（AD）是一种与精神衰退和痴呆有关的慢性神经疾病。有几项研究专注于研究疾病的分子基础，这导致了几个致病基因和相关风险等位基因的鉴定。对不同人群的这些研究和发现进行复制非常重要。
对来自沙特阿拉伯的 117 例家族性和散发性 AD 病例进行分子评估。
通过直接测序三个已知的 AD 致病基因（PSEN1、PSEN2 和 APP）以及 AD 相关基因 SORL1 的编码区，对所有患者进行点突变的全面筛查。所有患者还进行了 APOE 等位基因的基因分型。对两个新的 SORL1 变体进行了计算机模拟的 3D 蛋白质结构分析。
我们在所有研究的基因中总共发现了 8 个潜在的致病性错义变异。其中 5 个变异以前没有报道过，包括 SORL1 中的 4 个（p.Val297Met、p.Arg1084Cys、p.Asp1100Asn 和 p.Pro1213Ser）和 APP 中的 1 个（p.Glu380Lys）。APOE-ɛ4 等位基因的频率为总调查病例的 21.37%。对两个新的 SORL1 错义变异（p.Pro1213Ser 和 p.Arg1084Cys）的计算机模拟 3D 蛋白质结构分析表明，这些变异可能影响蛋白质的折叠并扰乱其结构。
我们对已知基因的开放阅读框进行了全面分析，在 18/117 例病例中发现了潜在的致病性罕见变异。我们发现 AD 主要基因（PSEN1、PSEN2 和 APP）中的点突变在我们的患者队列中代表性不足。我们的结果证实了 SORL1 参与了家族性和散发性 AD 病例。
