Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia
Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia
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DOI：
10.1136/jmg.2005.039230
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Yahyaoui, M
中科院分区：
文献类型：
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作者：
Bouhouche, A;Benomar, A;Yahyaoui, M
工作背景：麻痹性截瘫是一种非常罕见的常染色体显性和隐性遗传疾病。我们先前将常染色体隐性遗传形式的基因座定位在染色体5 p上标记D5 S2048和D5 S648之间的25 cM间隔处。在此候选区间内，编码胞质伴侣蛋白复合物肽-1（CCT）δ亚基的Cct 5基因是最明显的候选基因，因为编码CCT δ亚基的Cct 4基因突变已被报道与常染色体隐性遗传性肢端损伤（mf）大鼠突变体的肢端损伤感觉神经病相关。一个摩洛哥血缘家庭，有四名患者表现出与痉挛性截瘫相关的感觉神经损伤。为了确定致病基因，Cct 5基因的11个编码外显子的突变进行了筛选，通过直接测序的所有家庭成员，包括4名患者，父母，和6个在风险relations.Results：Cct 5基因的序列分析显示，在外显子4的错义A492 G突变，导致在精氨酸氨基酸147的高度保守的组氨酸取代。有趣的是，R147是不存在的384个对照匹配的染色体tested.Conclusion：这是第一个致病突变，已被确定在人类CCT亚基基因的mf大鼠突变体可以作为一种动物模型，为研究这些伴侣蛋白病。
Background: Mutilating sensory neuropathy with spastic paraplegia is a very rare disease with both autosomal dominant and recessive modes of inheritance. We previously mapped the locus of the autosomal recessive form to a 25 cM interval between markers D5S2048 and D5S648 on chromosome 5p. In this candidate interval, the Cct5 gene encoding the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (CCT) was the most obvious candidate gene since mutation in the Cct4 gene encoding the CCT delta subunit has been reported to be associated with autosomal recessive mutilating sensory neuropathy in mutilated foot (mf) rat mutant.Methods: A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated. To identify the disease causing gene, the 11 coding exons of the Cct5 gene were screened for mutations by direct sequencing in all family members including the four patients, parents, and six at risk relatives.Results: Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4 that results in the substitution of a highly conserved histidine for arginine amino acid 147. Interestingly, R147 was absent in 384 control matched chromosomes tested.Conclusion: This is the first disease causing mutation that has been identified in the human CCT subunit genes; the mf rat mutant could serve as an animal model for studying these chaperonopathies.