Casarin Alberto, Jimenez-Ortega Jose Carlos, Trevisson Eva, Pertegato Vanessa, Doimo Mara, Ferrero-Gomez Maria Lara, Abbadi Sara, Artuch Rafael, Quinzii Catarina, Hirano Michio, Basso Giuseppe, Ocaña Carlos Santos, Navas Placido, Salviati Leonardo
Clinical Genetics Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
Biochem Biophys Res Commun. 2008 Jul 18;372(1):35-9. doi: 10.1016/j.bbrc.2008.04.172. Epub 2008 May 12.
Defects in genes involved in coenzyme Q (CoQ) biosynthesis cause primary CoQ deficiency, a severe multisystem disorders presenting as progressive encephalomyopathy and nephropathy. The COQ4 gene encodes an essential factor for biosynthesis in Saccharomyces cerevisiae. We have identified and cloned its human ortholog, COQ4, which is located on chromosome 9q34.13, and is transcribed into a 795 base-pair open reading frame, encoding a 265 amino acid (aa) protein (Isoform 1) with a predicted N-terminal mitochondrial targeting sequence. It shares 39% identity and 55% similarity with the yeast protein. Coq4 protein has no known enzymatic function, but may be a core component of multisubunit complex required for CoQ biosynthesis. The human transcript is detected in Northern blots as a approximately 1.4 kb single band and is expressed ubiquitously, but at high levels in liver, lung, and pancreas. Transcription initiates at multiple sites, located 333-23 nucleotides upstream of the ATG. A second group of transcripts originating inside intron 1 of the gene encodes a 241 aa protein, which lacks the mitochondrial targeting sequence (isoform 2). Expression of GFP-fusion proteins in HeLa cells confirmed that only isoform 1 is targeted to mitochondria. The functional significance of the second isoform is unknown. Human COQ4 isoform 1, expressed from a multicopy plasmid, efficiently restores both growth in glycerol, and CoQ content in COQ4(null) yeast strains. Human COQ4 is an interesting candidate gene for patients with isolated CoQ(10) deficiency.
参与辅酶Q（CoQ）生物合成的基因缺陷会导致原发性CoQ缺乏，这是一种严重的多系统疾病，表现为进行性脑肌病和肾病。COQ4基因编码酿酒酵母生物合成中的一个必需因子。我们已经鉴定并克隆了其人类同源基因COQ4，它位于9号染色体q34.13上，转录成一个795个碱基对的开放阅读框，编码一个265个氨基酸（aa）的蛋白质（异构体1），其N端有一个预测的线粒体靶向序列。它与酵母蛋白有39%的同一性和55%的相似性。Coq4蛋白没有已知的酶功能，但可能是CoQ生物合成所需的多亚基复合物的核心成分。在Northern印迹中检测到人类转录本为一条约1.4kb的单带，且广泛表达，但在肝脏、肺和胰腺中表达水平较高。转录起始于多个位点，位于ATG上游333 - 23个核苷酸处。该基因内含子1内部产生的第二组转录本编码一个241个氨基酸的蛋白质，该蛋白质缺乏线粒体靶向序列（异构体2）。在HeLa细胞中GFP融合蛋白的表达证实只有异构体1靶向线粒体。第二种异构体的功能意义尚不清楚。从多拷贝质粒表达的人类COQ4异构体1能有效恢复COQ4（缺失）酵母菌株在甘油中的生长以及CoQ含量。人类COQ4是孤立性CoQ(10)缺乏患者的一个有趣的候选基因。
