Scacco Salvatore, Petruzzella Vittoria, Budde Sandy, Vergari Rosaria, Tamborra Rosanna, Panelli Damiano, van den Heuvel Lambert P, Smeitink Jan A, Papa Sergio
Department of Medical Biochemistry and Medical Biology, University of Bari, 70124 Bari, Italy.
J Biol Chem. 2003 Nov 7;278(45):44161-7. doi: 10.1074/jbc.M307615200. Epub 2003 Aug 27.
Presented is a study of the impact on the structure and function of human complex I of three different homozygous mutations in the NDUFS4 gene coding for the 18-kDa subunit of respiratory complex I, inherited by autosomal recessive mode in three children affected by a fatal neurological Leigh-like syndrome. The mutations consisted, respectively, of a AAGTC duplication at position 466-470 of the coding sequence, a single base deletion at position 289/290, and a G44A nonsense mutation in the first exon of the gene. All three mutations were found to be associated with a defect of the assembly of a functional complex in the inner mitochondrial membrane. In all the mutations, in addition to destruction of the carboxyl-terminal segment of the 18-kDa subunit, the amino-terminal segment of the protein was also missing. In the mutation that was expected to produce a truncated subunit, the disappearance of the protein was associated with an almost complete disappearance of the NDUFS4 transcript. These observations show the essential role of the NDUFS4 gene in the structure and function of complex I and give insight into the pathogenic mechanism of NDUFS4 gene mutations in a severe defect of complex I.
本文呈现了一项关于三个不同纯合突变对人类复合物I的结构和功能影响的研究。这三个突变存在于编码呼吸复合物I的18 kDa亚基的NDUFS4基因中，以常染色体隐性模式遗传给三名患有致命神经性 Leigh 样综合征的儿童。这些突变分别为：编码序列第466 - 470位的AAGTC重复、第289/290位的单碱基缺失以及该基因第一个外显子中的G44A无义突变。所有这三个突变均与线粒体内膜中功能性复合物组装缺陷相关。在所有突变中，除了18 kDa亚基的羧基末端片段被破坏外，该蛋白质的氨基末端片段也缺失。在预期会产生截短亚基的突变中，蛋白质的消失与NDUFS4转录本几乎完全消失相关。这些观察结果表明了NDUFS4基因在复合物I的结构和功能中的重要作用，并深入了解了NDUFS4基因突变在复合物I严重缺陷中的致病机制。
