IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40139 Bologna, Italy.
Viruses. 2022 Feb 10;14(2):367. doi: 10.3390/v14020367.
Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrP), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrP profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV).
变异性蛋白酶敏感朊病毒病是一种非常罕见的、可能被低估的散发性朊病毒病，其特征是具有异质性且常常是非特异性的临床和病理学特征，给诊断带来挑战。我们报告了对三个具有不同朊蛋白基因（）色氨酸（M）/缬氨酸（V）多态性密码子 129 不同基因型标志性病例的综合分析结果。临床、生化和神经病理学发现强调了宿主遗传背景作为表型调节剂的重要作用。特别是，密码子 129 对病理性朊蛋白（PrP）的理化性质具有显著影响，尤其是对蛋白酶 K（PK）消化的敏感性（VV>MV>MM），这对包括 PK 消化和免疫印迹后 PrP 谱的三个主要片段（即分别为 19、17 和 7 kDa）产生了不同的影响。这反过来又与 PK 消化后 19 kDa 和 7 kDa 片段之间的比值存在显著差异相关，其中 MM 病例的比值最高，VV 病例的比值最低。大脑和小脑 PrP 微斑免疫组织化学的相对含量也与密码子 129 基因型具有相似的关联（即 VV>MV>MM）。除了在我们测试的唯一脑脊液样本（来自 129VV 患者）中通过实时震颤诱导转换测定检测到朊病毒接种活性外，临床症状和诊断研究结果是非特异性的。
