Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome
Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome
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DOI：
10.1007/s004390051033
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发表时间：
2000-02-01
期刊：
影响因子：
5.3
通讯作者：
Rustin, P
中科院分区：
文献类型：
--
作者：
Parfait, B;Chretien, D;Rustin, P
琥珀酸脱氢酶(SDH)缺乏是Leigh综合征(LS)的一个次要原因。值得注意的是，4年前在患有LS和SDH缺乏症的两个兄弟姐妹中报告了第一个核编码呼吸链成分突变，即SDH黄素蛋白(FP)亚单位基因5p15拷贝的突变。我们现在报告一例新的LS和SDH缺乏症患者。由于FP基因的两个拷贝存在于人类基因组中，我们首先确定了这两个拷贝的完整结构。这使得我们能够在3q39拷贝中识别出1个碱基对的缺失，从而产生了一个移码，确认了第二个拷贝是假基因。我们还对5p15基因的启动子区域进行了测序，并对患者的突变进行了筛选。对患者的FP-SDH基因进行测序，我们只能确定一个杂合的C-T转换，将一个等位基因中的丙氨酸改变为缬氨酸。这一转变在患者父亲中被发现是杂合子，但在150名对照中缺失。将相应的突变基因导入人FP缺陷细胞，未能恢复正常的SDH活性，证实了该突变的有害作用。第二个等位基因遗传自母亲，携带A到C替换，将蛋氨酸翻译起始密码子改变为亮氨酸。该突变转录本仅占FP转录本总量的10%，提示该转录本不稳定。到目前为止，由于SDH的FP基因突变而导致的复合体II活性的深刻缺陷仅以LS的形式存在，鉴于这种典型的管家基因在人类中的普遍表达，这是一个引人注目的观察结果。
Succinate dehydrogenase (SDH) deficiency represents a minor cause of Leigh syndrome (LS). Noticeably, the first mutation in a nuclear-encoded respiratory chain component, a mutation in the 5p15 copy of the flavoprotein (Fp) subunit gene of the SDH, was reported 4 years ago in two siblings with LS and SDH deficiency. We now report a new patient with LS and SDH deficiency. Because two copies of the Fp gene are present in the human genome, we first determined the complete structure of these two copies. This allowed us to identify a 1 bp deletion creating a frameshift ill the 3q39 copy, confirming that this second copy was a pseudogene. We also sequenced the promoter region of the 5p15 gene and, in addition, screened for mutations in the patient. Sequencing of the Fp SDH cDNA in the patient only allowed us to identify a heterozygous C to T transition, changing an alanine to a valine in one allele. This transition was found to be heterozygous in the patient's father but was absent from 150 controls. Transfection of the corresponding mutant cDNA into human Fp-deficient cells failed to restore normal SDH activity, confirming the deleterious effect of this mutation. The second allele, inherited from the mother, carried an A to C substitution changing the methionine translation initiation codon to a leucine. This mutant transcript represented only 10% of total Fp transcript suggesting instability of this transcript. So far, profound deficiencies in complex II activity resulting from mutations in the Fp gene of the SDH present only as LS, a striking observation in view of the ubiquitous expression of this typical housekeeping gene in humans.