Spiekerkoetter Ute, Eeds Angela, Yue Zou, Haines Jonathan, Strauss Arnold W, Summar Marshall
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Hum Mutat. 2002 Dec;20(6):447-51. doi: 10.1002/humu.10142.
The mitochondrial trifunctional protein (TFP) is an enzyme complex of the fatty acid beta-oxidation cycle composed of an alpha- and a beta-subunit. The two encoding genes are located in the same region on chromosome 2 (2p23). TFP deficiency due to either alpha- or beta-subunit mutations is characterized by mutational and phenotypic heterogeneity with severe, early-onset, cardiac forms and milder, later-onset, myopathic phenotypes. In two unrelated patients with lethal TFP deficiency, we delineated apparently homozygous alpha-subunit mutations that were present in heterozygous form in both mothers, but not in either biological father. We performed a microsatellite repeat analysis of both patients and their parents using seven chromosome 2-specific polymorphic DNA markers and four nonchromosome 2 markers. In both patients, two chromosome 2-specific markers demonstrated maternal isodisomy of chromosome 2. The other five chromosome 2-specific markers were noninformative in each patient. Inheritance of alleles from chromosomes 4, 5, and 7 was consistent with paternity. These results explain the apparently anomalous pattern of transmission. Six of our 12 known TFP-deficient patients with alpha-subunit mutations have disease due to homozygous changes and two of them via the mechanism of uniparental disomy (UPD) (16.7%). For very rare autosomal recessive diseases, UPD may represent a common mechanism. This study emphasizes the need to confirm mutations in parents whenever possible. TFP deficiency is another disorder that has become manifest due to isodisomy of chromosome 2. This information will impact genetic counseling for these families, reducing greatly the 25% risk normally used for recessive disorders.
线粒体三功能蛋白（TFP）是脂肪酸β氧化循环中的一种酶复合物，由α亚基和β亚基组成。这两个编码基因位于2号染色体的同一区域（2p23）。由于α亚基或β亚基突变导致的TFP缺乏症具有突变和表型异质性，表现为严重的早发性心脏型和较轻的晚发性肌病型表型。在两名患有致死性TFP缺乏症的无关患者中，我们确定了明显纯合的α亚基突变，这两个突变在两位母亲中以杂合形式存在，但在两位生物学父亲中均未出现。我们使用7个2号染色体特异性多态性DNA标记和4个非2号染色体标记对两名患者及其父母进行了微卫星重复分析。在两名患者中，两个2号染色体特异性标记显示2号染色体的母源性等二体性。另外五个2号染色体特异性标记在每位患者中均无信息价值。来自4号、5号和7号染色体的等位基因遗传与亲子关系一致。这些结果解释了明显异常的遗传模式。在我们已知的12例患有α亚基突变的TFP缺乏症患者中，有6例因纯合变化而患病，其中2例是通过单亲二体（UPD）机制患病（16.7%）。对于非常罕见的常染色体隐性疾病，UPD可能是一种常见机制。本研究强调了尽可能对父母的突变进行确认的必要性。TFP缺乏症是另一种因2号染色体等二体性而显现的疾病。这一信息将影响这些家庭的遗传咨询，大大降低通常用于隐性疾病的25%的风险。
