CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures
CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures
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DOI：
10.1016/j.ajhg.2007.12.022
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发表时间：
2008-03-01
影响因子：
9.8
通讯作者：
Roetig, Agnes
中科院分区：
文献类型：
--
作者：
Mollet, Julie;Delahodde, Agnes;Roetig, Agnes
辅酶Q（10）（CoQ（10））在氧化磷酸化（OXPHOS）中起关键作用，因为它在呼吸链的各种酶和细胞色素片段之间分配电子。原发性辅酶Q10缺乏症是一种临床异质性疾病，提示遗传异质性，并且先前已经鉴定了几种疾病基因。CABC 1基因，也称为COQ 8或ADCK 3，是酵母ABC 1/COQ 8基因的人类同源物，是参与泛醌生物合成途径的众多基因之一。Abc 1/Coq 8蛋白的确切功能尚不清楚，但该蛋白被归类为推定的蛋白激酶。我们在这里报告四个泛醌缺乏症患者在三个不同的家庭CABC 1基因突变。这些患者表现出类似的进行性神经系统疾病，伴有小脑萎缩和癫痫发作。在所有情况下，酶学研究指出，泛醌缺乏症。辅酶Q（10）缺乏症通过肌肉中泛醌含量的降低来证实。各种错义突变（R213 W、G272 V、G272 D和E551 K）修饰蛋白质的高度保守氨基酸和Ibp移码插入c. [1812_1813insG]。将错义突变引入酵母ABC 1/COQ 8基因，并在其中ABC 1/COQ 8基因缺失的酿酒酵母菌株中表达。所有的错义突变导致呼吸表型，在甘油培养基上没有或减少生长，并严重减少泛醌合成，表明这些突变改变蛋白质功能。
Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q10 deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.