Department of Neurology University of Washington Seattle Washington.
Division of Medical Genetics Department of Medicine University of Washington Seattle Washington.
Ann Clin Transl Neurol. 2019 Mar 10;6(4):762-777. doi: 10.1002/acn3.755. eCollection 2019 Apr.
Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (), presenilin 2 (), and amyloid precursor protein (). Previously, we reported a rare frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates.
We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families.
Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs11 fibroblasts secrete less A compared to controls, indicating abnormal -secretase activity. Analysis of transcript levels in brain tissue revealed alternatively spliced products in patient brain as well as in sporadic AD and age-matched control brain.
These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel alternative transcripts in addition to previously reported splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.
常染色体显性家族性阿尔茨海默病（AD）是由早老素 1 (), 早老素 2 () 和淀粉样前体蛋白 () 的变异引起的。此前，我们报道了一个早发性 AD 病例中罕见的 移码变异（PSEN2 p.K115Efs*11）。在这项研究中，我们对第二个具有相同变异的家族进行了特征描述，并分析了来自患者成纤维细胞和脑裂解物的细胞转录物。
我们结合基因组学、神经病理学、临床和分子技术，对两个家族的 PSEN2 K115Efs*11 变异进行了特征描述。
神经病理学和临床评估证实了携带 PSEN2 K115Efs11 变异的两个个体的 AD 诊断。从变异等位基因中可检测到截短的转录本，而与对照相比，野生型 转录本和蛋白的水平降低。评估该变异的生物学后果的功能研究表明，PSEN2 K115Efs11 成纤维细胞分泌的 A 比对照少，表明 -分泌酶活性异常。对脑组织中 转录本水平的分析显示，患者脑组织以及散发性 AD 和年龄匹配的对照脑组织中存在可替代性的 产物。
这些数据表明 PSEN2 K115Efs*11 是与 AD 相关的一种可能的致病性变异。除了与散发性 AD 相关的先前报道的 剪接异构体外，我们还发现了新的 替代转录本。在移码的情况下，这些替代转录本返回规范的阅读框，可能产生有害的蛋白产物。我们的发现表明 变异可能影响 AD 发病机制的新的潜在机制，突出了遗传对疾病风险的影响的复杂性。
