在零星的人类原体疾病中对PRNP体和生殖系变体进行神经病理导向的分析
Gannon A McDonough1, Yuchen Cheng2,3, Katherine Morillo2
1Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
bioRxiv : the preprint server for biology
|July 9, 2024
概括
在PRNP基因的体质突变不是 Sporadic Creutzfeldt-Jakob病 (sCJD) 的重要原因. 深度测序在sCJD患者中没有发现这些突变的证据,这表明其他因素驱动了这种神经退行性疾病.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 克鲁茨菲尔特-雅各布病 (CJD) 是最常见的人类子疾病,与PRNP基因编码的错误折叠子蛋白 (PrP) 有关.
- 散发性CJD (sCJD) 占~85%的病例,其原因仍然未知.
- 在衰老期间在神经元中积累的体质突变被假设为sCJD的潜在原因.
研究的目的:
- 调查PRNP基因体质突变有助于零星CJD的发展的假设.
- 用深度DNA测序分析PRNP体质突变在sCJD病例和年龄匹配对照中.
主要方法:
- 在205例sCJD病例和170例对照中对PRNP基因进行深度DNA测序.
- 包括5例海登海因变异散发性CJD (H-sCJD) 病例,检查多个大脑区域.
- 使用多个独立的原料PCR测序 (MIPP-Seq) 测序,中位深度>5,000X,并使用MosaicHunter进行变异分析.
主要成果:
- 在sCJD病例中,包括H-sCJD受影响地区,没有发现PRNP的真实体变异.
- 对原始测序数据的分析表明,在sCJD患者中,已知致病性生殖系变体 (P102L,D178N,E200K) 的丰富没有发生.
- 该研究检测到常见的多态生殖系变异,但没有特定疾病的体质突变.
结论:
- 在PRNP基因中的克隆性体性突变似乎在零星CJD的发病过程中没有发挥重要作用.
- 这些发现挑战了PRNP体质突变是sCJD的基础的假设,特别是像H-sCJD这样的焦点表现.
- 需要进一步的研究来阐明零星的病的未知原因.
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