Rossi G, Giaccone G, Giampaolo L, Iussich S, Puoti G, Frigo M, Cavaletti G, Frattola L, Bugiani O, Tagliavini F
Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
Neurology. 2000 Aug 8;55(3):405-10. doi: 10.1212/wnl.55.3.405.
To investigate the role of a short insertional mutation in the prion protein (PrP) gene (PRNP) in prion disease pathogenesis.
The genetic forms of Creutzfeldt-Jakob disease (CJD) are associated with point or insertional mutations in PRNP. Whereas patients with five, six, seven, eight, and nine extra octapeptide repeats show an autosomal dominant pattern of inheritance and features of CJD, Gerstmann-Sträussler-Scheinker disease, or atypical dementia, patients with one, two, or four extra repeats have typical CJD and lack a family history of neurologic disorder.
A genetic, neuropathologic, and biochemical study was carried out in a 65-year-old patient with clinical features of sporadic CJD.
A novel four extra-repeat insertional mutation of PRNP was found in the patient and in his 59-year-old healthy sister. The patient showed spongiosis, nerve cell loss, and gliosis associated with diffuse PrP immunoreactivity in the cerebral cortex, subcortical gray structures, and cerebellum. A peculiar aspect was the presence of focal PrP deposits in the basal ganglia and hypothalamus, superimposed to diffuse PrP immunoreactivity. The biochemical analysis revealed that both mutant and wild-type PrP participated in the pathologic process, and that the protease-resistant core of the altered PrP isoforms was distinct from that observed in sporadic, acquired, and other genetic forms of CJD.
These findings support the view that the four extra-repeat insertion in PRNP is a pathogenic mutation with low penetrance rather than a benign polymorphism, and suggest that this mutation results in the formation of a distinct PrP conformer.
研究朊病毒蛋白（PrP）基因（PRNP）中的短插入突变在朊病毒病发病机制中的作用。
克雅氏病（CJD）的遗传形式与PRNP中的点突变或插入突变有关。虽然有五个、六个、七个、八个和九个额外八肽重复序列的患者表现出常染色体显性遗传模式以及CJD、格斯特曼-施特劳斯勒-谢inker病或非典型痴呆的特征，但有一个、两个或四个额外重复序列的患者患有典型的CJD且无神经疾病家族史。
对一名具有散发性CJD临床特征的65岁患者进行了遗传学、神经病理学和生物化学研究。
在该患者及其59岁的健康姐姐中发现了一种新的PRNP四个额外重复序列的插入突变。患者表现出海绵状变性、神经细胞丢失和胶质细胞增生，伴有大脑皮质、皮质下灰色结构和小脑中弥漫性PrP免疫反应性。一个特殊的方面是基底神经节和下丘脑中存在局灶性PrP沉积，叠加在弥漫性PrP免疫反应性之上。生化分析表明，突变型和野生型PrP均参与了病理过程，并且改变后的PrP异构体的蛋白酶抗性核心与散发性、获得性及其他遗传形式的CJD中观察到的不同。
这些发现支持以下观点，即PRNP中的四个额外重复序列插入是一种低外显率的致病突变而非良性多态性，并表明该突变导致形成一种独特的PrP构象异构体。
