FATAL FAMILIAL INSOMNIA, A PRION DISEASE WITH A MUTATION AT CODON-178 OF THE PRION PROTEIN GENE
FATAL FAMILIAL INSOMNIA, A PRION DISEASE WITH A MUTATION AT CODON-178 OF THE PRION PROTEIN GENE
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DOI：
10.1056/nejm199202133260704
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发表时间：
1992-02-13
影响因子：
158.5
通讯作者：
GAMBETTI, P
中科院分区：
文献类型：
--
作者：
MEDORI, R;TRITSCHLER, HJ;GAMBETTI, P
背景 我们以前描述了一个家庭的两名成员受到明显的遗传决定的致命疾病的影响，其临床特征是进行性失眠，自主神经功能障碍和运动体征，病理特征是丘脑前腹核和背内侧核严重萎缩。其他五名死于这种疾病的家庭成员，我们将其称为“致命的家族性失眠症”，他们有更广泛的神经病理学变化，这表明致命的家族性失眠症可能是一种朊病毒疾病。方法。 我们使用朊病毒蛋白（PrP）的抗体进行斑点和蛋白质印迹分析，有和没有蛋白酶K，在尸检中获得的脑组织从两个致命的家族性失眠症患者，三个散发性克雅氏病患者，和六个对照组。对两例家族性致死性失眠症患者的PrP基因编码区进行扩增和测序。对33份该属成员的PrP DNA进行限制性酶切分析。 蛋白酶耐药PrP被发现在这两个致命的家族性失眠症患者，但蛋白酶耐药片段的大小和数量不同，从克雅氏病。在家族性致死性失眠症中，所有4名受影响的成员和29名未受影响的成员中的11名在PrP密码子178中发生了点突变，导致天冬氨酸被天冬酰胺取代，并消除了Tth111 I限制性位点。连锁分析显示该点突变与疾病关系密切（θ = 0时，最大lod值为3.4）。 致死性家族性失眠症是一种朊病毒疾病，其PrP基因的密码子178发生突变，但疾病表型似乎与先前描述的具有相同点突变的家族性失眠症不同。
Background. We previously described two members of a family affected by an apparently genetically determined fatal disease characterized clinically by progressive insomnia, dysautonomia, and motor signs and characterized pathologically by severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Five other family members who died of this disease, which we termed "fatal familial insomnia," had broader neuropathologic changes suggesting that fatal familial insomnia could be a prion disease.Methods. We used antibodies to prion protein (PrP) to perform dot and Western blot analyses, with and without proteinase K, on brain tissue obtained at autopsy from two patients with fatal familial insomnia, three patients with sporadic Creutzfeldt-Jakob disease, and six control subjects. The coding region of the PrP gene was amplified and sequenced in the samples from the two patients with fatal familial insomnia. Restriction-enzyme analysis was carried out with amplified PrP DNA from 33 members of the kindred.Results. Protease-resistant PrP was found in both patients with fatal familial insomnia, but the size and number of protease-resistant fragments differed from those in Creutzfeldt-Jakob disease. In the family with fatal familial insomnia, all 4 affected members and 11 of the 29 unaffected members had a point mutation in PrP codon 178 that results in the substitution of asparagine for aspartic acid and elimination of the Tth111 I restriction site. Linkage analysis showed a close relation between the point mutation and the disease (maximal lod score, 3.4 when theta was zero).Conclusions. Fatal familial insomnia is a prion disease with a mutation in codon 178 of the PrP gene, but the disease phenotype seems to differ from that of previously described kindreds with the same point mutation.