TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy
TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy
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DOI：
10.1038/jhg.2016.149
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发表时间：
2017-04-01
影响因子：
3.5
通讯作者：
Nunoi, Hiroyuki
中科院分区：
文献类型：
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作者：
Ikeda, Toshio;Nakahara, Akihiko;Nunoi, Hiroyuki
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种由运动神经元存活基因突变引起的常染色体隐性遗传神经退行性疾病。SMA的变异形式伴有其他临床表现，被归类为非典型SMA，认为是由尚未确定的致病基因变异引起的。在这里，我们介绍了两个兄弟姐妹的临床表现与SMA变异，其次是进行性脑萎缩，和全外显子组测序分析的结果，进行家庭四重奏，以确定潜在的致病变异。我们确定了两个候选的纯合错义变体，R942 Q的微管蛋白折叠辅因子D（TBCD）基因和H250 Q的溴邻近同源结构域和卷曲螺旋1（BAHCC 1）基因，位于染色体17q25.3的间隔为1.4 Mbp。两种变体的计算机分析表明，TBCD而不是BAHCC 1可能是致病基因（TBCD敏感性，0.68;特异性，0.97; BAHCC 1敏感性，1.00;特异性，0.00）。因此，我们的研究结果表明，TBCD是一个可能的新的候选基因的非典型SMA进行性脑萎缩。预测TBCD对运动神经元以及中枢神经系统中的微管蛋白完整性具有重要功能。
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.