一种新的复合杂合突变导致3-甲基巴豆酰辅酶A羧化酶缺乏症

A novel compound heterozygous mutation causing 3-methylcrotonyl-CoA carboxylase deficiency

目的对1例新生儿筛查疑似3-甲基巴豆酰辅酶A羧化酶缺乏症的患儿进行基因突变分析，揭示其分子病因。方法PCR结合Sanger测序对患儿MCCC1基因和MCCC2基因的全部外显子及其旁侧序列进行分析，检测其中可能存在的基因变异，应用SIFT、PolyPhen-2在线软件预测突变对蛋白功能影响，并查询比对突变所在位置在不同物种间的保守性。采用Human Splicing Finder和Swiss—PdbViewer4．1．0软件分析基因变异导致疾病发生的可能机制。结果患儿MCCC1基因检测到两个杂合突变，分别为C．539G〉T（p．G180V）和C．704—711del（P．A235Vfs＊4），家系分析显示，前者遗传于父亲，后者遗传于母亲。这两个突变均可改变蛋白质的结构，从而对MCC蛋白功能造成影响。结论MCCC1基因c．539G〉T（p．G180V）和C．704_711del（P．A235Vfs＊4）复合杂合突变可能是导致患儿MCCD的分子病因。

Objective To explore the molecular mechanism for a boy suspected with 3- methylcrotonyl-CoA carboxylase deficiency by neonatal screening. Methods PCR and Sanger sequencing were used to identify potential mutations of MCCC1 and MCCC2 genes. SIFT and Polyphen-2 software was used to predict the effect of variant on the protein function and conservation of the variant across various species. Human Splicing Finder and Swiss-PdbViewer4.1.0 were applied to analyze the possible mechanism of the variant. Results For the proband, a compound heterozygous mutation was discovered in the MCCC1 gene, namely c. 539G〉T （p. G180V） and c. 704_711del （p. A235Vfs ＊ 4）, which were inherited from his father and mother, respectively. The two mutations have disrupted the protein conformation, which in turn may impact the function of MCC protein. Conclusion The compound heterozygous mutations of the MCCC1 gene may contribute to the 3-methylcrotonyl-CoA carboxylase deficiency manifested by the patient.