Emerging evidence of coding mutations in the ubiquitin-proteasome system associated with cerebellar ataxias.
Emerging evidence of coding mutations in the ubiquitin-proteasome system associated with cerebellar ataxias.
复制标题
DOI：
10.1038/hgv.2014.18
复制
发表时间：
2014
影响因子：
1.5
通讯作者：
Schisler JC
中科院分区：
文献类型：
--
作者：
Ronnebaum SM;Patterson C;Schisler JC
小脑性共济失调是一种由小脑变性引起的平衡、协调和步态障碍的疾病。与CA相关的突变影响功能不同的基因；此外，在许多患者中，给定CA的潜在遗传基础尚不清楚。外显子组测序已经成为发现新的基因突变的一种经济有效的技术，包括常染色体隐性CA(ARCA)。最近的五项研究描述了如何对不同的ARCA患者进行外显子组测序，发现了STUB1基因的14个独特突变，STUB1基因编码Hsp70相互作用蛋白(CHIP)的羧基末端。CHIP通过伴侣和泛素连接酶的活性介导蛋白质质量控制，并参与减轻几种神经退行性疾病的蛋白质毒性。然而，这些最近的研究将STUB1突变与各种形式的共济失调联系起来，这是第一个表明CHIP直接参与人类疾病发展的迹象。类似的外显子测序研究已经发现了与CA和其他神经疾病相关的泛素相关蛋白的新突变。这篇综述提供了CA的概述，描述了外显子组测序的优点和局限性，概述了新发现的STUB1突变，并从理论上阐明了CHIP和其他泛素相关蛋白如何发挥作用以防止神经恶化。
Cerebellar ataxia (CA) is a disorder associated with impairments in balance, coordination, and gait caused by degeneration of the cerebellum. The mutations associated with CA affect functionally diverse genes; furthermore, the underlying genetic basis of a given CA is unknown in many patients. Exome sequencing has emerged as a cost-effective technology to discover novel genetic mutations, including autosomal recessive CA (ARCA). Five recent studies that describe how exome sequencing performed on a diverse pool of ARCA patients revealed 14 unique mutations in STUB1, a gene that encodes carboxy terminus of Hsp70-interacting protein (CHIP). CHIP mediates protein quality control through chaperone and ubiquitin ligase activities and is implicated in alleviating proteotoxicity in several neurodegenerative diseases. However, these recent studies linking STUB1 mutations to various forms of ataxia are the first indications that CHIP is directly involved in the progression of a human disease. Similar exome-sequencing studies have revealed novel mutations in ubiquitin-related proteins associated with CA and other neurological disorders. This review provides an overview of CA, describes the benefits and limitations of exome sequencing, outlines newly discovered STUB1 mutations, and theorizes on how CHIP and other ubiquitin-related proteins function to prevent neurological deterioration.