Genetic basis of mitochondrial HMG-CoA synthase deficiency
Genetic basis of mitochondrial HMG-CoA synthase deficiency
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DOI：
10.1007/s004390100554
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发表时间：
2001-07-01
期刊：
影响因子：
5.3
通讯作者：
Hegardt, FG
中科院分区：
文献类型：
--
作者：
Aledo, R;Zschocke, J;Hegardt, FG
线粒体3-羟基-3-甲基戊二酰辅酶A合成酶缺陷(MHMGS)是一种隐性的酮体生成障碍，曾在两名儿童禁食期间诊断为低血糖低酮症昏迷。在这里，我们报告了第三个受这种疾病影响的患者的分子研究结果。对HMGCS2基因整个编码区的测序发现了两个错义突变，G212R和R500H。通过对亲本样本的分析，证实了孟德尔遗传，在200条对照染色体上没有发现这两个突变。在胞浆HMG缺陷细胞中的体外表达研究证实了功能相关性。而野生型HMGCS2基因可逆转甲氧戊酸的营养缺陷症，而突变体的cDNA则不能。这种疾病可以通过特定的临床和生化特征来识别，但很难通过酶学来证实，因为该基因只在肝脏和睾丸中表达。分子研究可能有助于或确认未来对受影响患者的诊断。
Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGS) is a recessive disorder of ketogenesis that has been previously diagnosed in two children with hypoglycaemic hypoketotic coma during fasting periods. Here, we report the results of molecular investigations in a third patient affected by this disease. Sequencing of the entire coding region of the HMGCS2 gene revealed two missense mutations, G212R and R500H. Mendelian inheritance was confirmed by the analysis of parental samples and neither of the mutations was found on 200 control chromosomes. Functional relevance was confirmed by in vitro expression studies in cytosolic HMGS-deficient cells. Whereas wild-type cDNA of the HMGCS2 gene reverted the auxotrophy for mevalonate, the cDNAs of the mutants did not. The disease may be recognised by specific clinical and biochemical features but it is difficult to confirm enzymatically since the gene is expressed only in liver and testis. Molecular studies may facilitate or confirm future diagnoses in affected patients.