Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2
Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2
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DOI：
10.1016/j.ajhg.2014.10.002
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发表时间：
2014-11-06
影响因子：
9.8
通讯作者：
Houlden, Henry
中科院分区：
文献类型：
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作者：
Cottenie, Ellen;Kochanski, Andrzej;Houlden, Henry
我们结合外显子组测序和连锁分析，调查了一个英国家庭，该家庭有两个 40 多岁的兄弟姐妹，患有隐性腓骨肌萎缩症 2 型 (CMT2)。免疫球蛋白解旋酶 mu 结合蛋白 2 (IGHMBP2) 基因中存在复合杂合突变。进一步测序发现共有11个CMT2家族具有隐性遗传的IGHMBP2基因突变。 IGHMBP2 突变通常会导致脊髓性肌萎缩症并伴有 1 型呼吸窘迫 (SMARD1)，大多数婴儿在一岁之前死亡。这里描述的患有 CMT2 的个体有缓慢进行性的无力、消瘦和感觉丧失，伴有 CMT2 典型的轴突神经病变，但没有明显的呼吸损害。 CMT2 中的分离 IGHMBP2 突变主要是基因 5' 区域的功能丧失性无义，以及最后一个外显子中的截短移码、错义或纯合移码突变。与 SMARD1 相比，CMT2 中的突变预计侵袭性较小，成纤维细胞和淋巴母细胞研究表明，CMT2 中的 IGHMBP2 蛋白水平显着高于 SMARD1，但低于对照，这表明临床表型差异与 IGHMBP2 蛋白水平有关。
Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-mu-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.