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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >Maple syrup urine disease. Complete defect of the E1 beta subunit of the branched chain alpha-ketoacid dehydrogenase complex due to a deletion of an 11-bp repeat sequence which encodes a mitochondrial targeting leader peptide in a family with the disease.
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Maple syrup urine disease. Complete defect of the E1 beta subunit of the branched chain alpha-ketoacid dehydrogenase complex due to a deletion of an 11-bp repeat sequence which encodes a mitochondrial targeting leader peptide in a family with the disease.

机译：枫糖浆尿病。该支链α-酮酸脱氢酶复合物的E1β亚基的完全缺陷是由于该疾病家族中编码线粒体靶向前导肽的11 bp重复序列的缺失所致。

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Branched chain alpha-ketoacid dehydrogenase (BCKDH) deficiency results in maple syrup urine disease (MSUD). We examined the molecular basis of familial cases of MSUD by analyzing the activity, subunit structure, mRNA sequence, and genome structure of the affected enzyme. The BCKDH activity in the proband with MSUD was approximately 6% of the normal control level. Immunoblot analysis revealed that the E1 beta subunit of BCKDH was absent and that the E1 alpha subunit of BCKDH was markedly reduced. We amplified the cDNAs of the E1 alpha subunit and the E1 beta subunit of the BCKDH complex obtained from cells of the patient, using the polymerase chain reaction method, then sequenced the amplified cDNAs. The deduced amino acid sequence for the E1 alpha subunit of the patient's cell was normal. An 11-bp deletion was identified in the region that encoded the mitochondrial targeting leader peptide in the E1 beta cDNA. This 11-bp sequence is found in the first exon of the BCKDH-E1 beta gene, as a direct tandem repeat. Amplification of genomic DNA revealed that the consanguineous parents were heterozygous for this mutant allele, and sister and brother of the patient with the disease were homozygous for this mutant allele. This 11-bp deletion mutation caused a change in the reading frame and the mature E1 beta protein was defective. These observations show the biological importance of the E1 beta subunit of BCKDH to maintain normal function of the enzyme activity. The absence of the E1 beta subunit results in instability of the E1 alpha subunit.
机译：支链α-酮酸脱氢酶（BCKDH）缺乏会导致枫糖浆尿病（MSUD）。我们通过分析受影响酶的活性，亚基结构，mRNA序列和基因组结构，检查了MSUD家族病例的分子基础。 MSUD的先证者的BCKDH活性约为正常对照水平的6％。免疫印迹分析表明，缺少BCKDH的E1β亚基，并且BCKDH的E1α亚基明显减少。我们使用聚合酶链反应方法扩增了从患者细胞中获得的BCKDH复合物的E1α亚基和E1β亚基的cDNA，然后对扩增的cDNA进行了测序。推导患者细胞的E1α亚基的氨基酸序列是正常的。在E1 beta cDNA中编码线粒体靶向前导肽的区域中鉴定出11 bp缺失。在BCKDH-E1 beta基因的第一个外显子中发现了这个11 bp的序列，作为直接串联重复序列。基因组DNA的扩增显示，近亲是该突变体等位基因的杂合子，患有该疾病的患者的姐姐和兄弟是该突变体等位基因的纯合子。这个11 bp的缺失突变导致阅读框发生变化，并且成熟的E1β蛋白存在缺陷。这些观察结果表明，BCKDH的E1β亚基对于维持酶活性的正常功能具有生物学重要性。 E1 beta亚基的缺失会导致E1 alpha亚基的不稳定。

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