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首页> 外文期刊>Human Molecular Genetics >Myopathy with lactic acidosis is linked to chromosome 12q23.3–24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect
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Myopathy with lactic acidosis is linked to chromosome 12q23.3–24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect

机译：乳酸性酸中毒肌病与12q23.3–24.11号染色体有关，由ISCU基因内含子突变引起，导致剪接缺陷

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摘要

We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3–24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene—ISCU—specifying a protein involved in iron–sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
机译：我们描述了与乳酸性酸中毒（HML）的遗传性肌病的基因的定位和鉴定。 HML的特征是身体机能低下，导致体力消耗过大，从而导致早期疲劳，呼吸困难和心。使用常染色体隐性遗传方式，我们将该性状映射到染色体12q23.3–24.11，最大lod得分为5.26。 1.6 Mb疾病关键区域包含一个明显的候选基因ISCU，该基因指定了一种参与铁硫簇组装的蛋白质。 IscU有两种同工型。由ISCU基因的不同剪接变体编码的一种胞质和一种线粒体。对所有外显子和内含子序列以及ISCU基因启动子的1000 bp突变进行分析，发现了一种对疾病单倍型具有特异性的内含子突变。该突变位于与干扰素刺激的反应元件（ISRE）具有同源性的区域，但我们看不到该突变对体外或体内表达水平的任何影响。但是，我们确实观察到了患者和对照之间剪接模式的巨大差异。如预期的那样，在对照中，mRNA主要为线粒体形式，而在患者中，较大的mRNA转录为主要。产物的测序表明，该突变激活了内含子5中的隐蔽剪接位点，导致含有100 bp内含子的异常mRNA。总而言之，我们的数据强烈表明，ISCU基因中的内含子突变导致错误的剪接mRNA，是该家族中乳酸性酸中毒的肌病原因。

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