2 ALPHA-SUBUNIT DONOR SPLICE-SITE MUTATIONS CAUSE HUMAN TRIFUNCTIONAL PROTEIN-DEFICIENCY
2 ALPHA-SUBUNIT DONOR SPLICE-SITE MUTATIONS CAUSE HUMAN TRIFUNCTIONAL PROTEIN-DEFICIENCY
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DOI：
10.1172/jci117894
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发表时间：
1995-05-01
影响因子：
15.9
通讯作者：
STRAUSS, AW
中科院分区：
文献类型：
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作者：
BRACKETT, JC;SIMS, HF;STRAUSS, AW
人三功能蛋白催化线粒体脂肪酸p氧化的三个步骤，包括长链3-羟基酰基辅酶a脱氢酶步骤。这种含有4个α和4个β亚基的异复合体缺乏可导致不明原因的婴儿猝死、雷氏样综合征、心肌病或骨骼肌病。我们利用反转录和PCR扩增其α亚基mRNA的方法，确定了新生儿表现和后来猝死的患者这种缺陷的分子基础。我们发现他的mRNA中普遍缺失外显子3 (71 bp)，这种缺失导致移码和非常早的过早终止，基因组DNA扩增表明该患者是一个复合杂合子，在外显子3后的5'供体剪接位点有两个不同的突变。父本遗传的+1不变位置G到a的翻转和母本遗传的+3位置a到G的突变，这两种等位基因突变都明显引起外显子3跳变，导致α亚基蛋白水平无法检测，三功能蛋白完全缺失，这是三功能蛋白缺乏的初始分子特征。
Human trifunctional protein catalyzes three steps in mitochondrial P-oxidation of fatty acids, including the long chain 3-hydroxyacyl-CoA dehydrogenase step. Deficiency of this heterocomplex, which contains 4 alpha and 4 beta subunits, causes sudden unexplained infant death, a Reye-like syndrome, cardiomyopathy, or skeletal myopathy. We determined the molecular basis of this deficiency in a patient with neonatal presentation and later sudden death using reverse transcription and PCR amplification of his alpha subunit mRNA. We demonstrated a universal deletion of exon 3 (71 bp) in his mRNA, This deletion causes a frameshift and very early premature termination, Amplification of genomic DNA demonstrated that the patient was a compound heterozygote with two different mutations in the 5' donor splice site following exon 3: a paternally inherited G to A transversion at the invariant position +1 and a maternally inherited A to G mutation at position +3, Both allelic mutations apparently cause exon 3 skipping, resulting in undetectable levels of alpha subunit protein, and complete loss of trifunctional protein, This is the initial molecular characterization of trifunctional protein deficiency.