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首页> 外文期刊>Orphanet journal of rare diseases >STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations
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STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations

机译：STUB1 / CHIP突变引起戈登·霍姆斯综合征，这是广泛的多系统神经变性的一部分：来自四个新突变的证据

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BackgroundCHIP, the protein encoded by STUB1 , is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome. MethodsWhole exome sequencing data-sets from n =?87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations. In-depth phenotyping by clinical evaluation and neuroimaging was performed in mutation carriers. ResultsWe identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87?=?2.3%). All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient. Diffusion tensor imaging revealed degeneration of manifold supra- and infratentorial tracts. ConclusionsOur findings provide clinical and imaging support for the notion that CHIP is a crucial converging point of manifold neurodegenerative processes, corresponding with its universal biological function in neurodegeneration. Further, our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1 . However, it does not present in isolation, but as part of a broad multisystemic neurodegenerative process. This supports the notion that STUB1 disease should be conceptualized not by historical or clinical syndromic names, but as a variable multisystemic disease defined by disturbed function of the underlying STUB1 gene, which translates into a multidimensional gradual spectrum of variably associated clinical signs and symptoms.
机译：背景技术CHIP是STUB1编码的蛋白质，是细胞蛋白质稳态的重要组成部分，并与多种神经退行性疾病的发病机理中涉及的几种关键蛋白质相互作用。这引起了这样一个假设：与先前报道的小脑性共济失调综合征相比，STUB1中的突变可能导致多系统性神经退行性表型。方法筛选来自两个共济失调队列的n =？87索引受试者的整个外显子组测序数据集，以寻找STUB1突变的个体。在突变携带者中通过临床评估和神经影像学进行了深入的表型分析。结果我们在来自两个指数家族的三个受影响受试者中鉴定出四个新的STUB1突变（频率2/87？=？2.3％）。这三名受试者均表现出严重的多系统表型，包括小脑性共济失调，重度痴呆，痉挛性四轻瘫，癫痫和自主神经功能障碍，以及一名索引患者的性腺功能减退。弥散张量成像显示歧管上和下管束变性。结论我们的发现为CHIP是多种神经退行性过程的关键收敛点这一观点提供了临床和影像学支持，与其在神经退行性变中的普遍生物学功能相对应。此外，我们的数据揭示了迄今为止报道的第二个患有共济失调加性腺功能减退的STUB1家族，表明戈登·霍姆斯综合症确实是STUB1的复发表现。然而，它不是孤立存在的，而是作为广泛的多系统神经退行性过程的一部分而存在的。这支持了STUB1疾病不应由历史或临床症状名称概念化的概念，而应作为由基础STUB1基因功能紊乱定义的可变多系统疾病，该疾病转化为多变的，逐步相关的临床体征和症状。

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