Department of Neurology, National Reference Center for Human Spongiform Encephalopathies, University Medical Center, Georg-August University, 37075 Goettingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), 37075 Goettingen, Germany.
Cells. 2023 Aug 12;12(16):2053. doi: 10.3390/cells12162053.
Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes ( and three protein coding genes and . These genetic variants are absent in FFI patients with early disease onset (19-40 years). The biological function of these genes and is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to , which may influence the onset of clinical symptoms in FFI.
致命家族性失眠症（FFI）是一种罕见的常染色体显性遗传朊病毒病，其发病年龄具有很大的可变性。其病因尚不清楚。在本研究中，我们旨在分析发病年龄不同的 FFI 患者除朊病毒蛋白基因（）以外的遗传风险因素。对 25 名 FFI 患者（D178N-129M）进行了全外显子组测序（WES）分析。通过 Reactome 进行基因本体论富集分析，生成与鉴定基因的生物学过程相关的假说。在本研究中，我们使用了一种针对数据特点定制的统计方法，鉴定了 19 个可能影响发病年龄的潜在基因变异。在两个假基因（和三个编码蛋白基因和中观察到潜在疾病调节风险基因座的证据。这些遗传变异在发病年龄较早（19-40 岁）的 FFI 患者中不存在。这些基因和的生物学功能与程序性细胞死亡、半胱天冬酶介导的细胞骨架蛋白裂解和细胞蛋白的凋亡裂解有关。总之，本研究首次提供了证据，证明除外，其他遗传风险因素可能影响 FFI 临床症状的发作。
