Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy
Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy
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DOI：
10.1086/379525
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发表时间：
2003-11-01
影响因子：
9.8
通讯作者：
Zerres, K
中科院分区：
文献类型：
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作者：
Senderek, J;Bergmann, C;Zerres, K
Charcot-Marie-Tooth病4C型（CMT 4C）是一种儿童期发病的遗传性运动和感觉神经病的脱髓鞘形式，与早发性脊柱侧凸和独特的雪旺细胞病理学相关。CMT 4C作为常染色体隐性遗传性状遗传，并已定位于染色体5 q23-q33上的13-cM连锁区间。通过纯合性定位和等位基因共享分析，我们将CMT 4C基因座精确到1.7 Mb的提示关键区域。随后，我们确定了突变的一个未知的转录，KIAA 1985，在12个家庭与常染色体隐性遗传性神经病。我们观察到八个不同的蛋白质截短突变和三个非保守的错义突变，影响通过进化保守的氨基酸。在所有的家庭中，我们确定了每个疾病等位基因的突变，无论是在纯合子或在复合杂合子状态。CMT 4C基因在包括外周神经组织在内的神经组织中强烈表达。翻译的蛋白质定义了一个新的蛋白质家族的未知功能与推定的直向同源物在脊椎动物中。比较序列比对表明，该蛋白质家族的成员含有多个SH 3和TPR结构域，可能参与蛋白质复合物的形成。
Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.