Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder
Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder
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DOI：
10.1093/hmg/ddp276
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发表时间：
2009-09-15
影响因子：
3.5
通讯作者：
Nijtmans, Leo G. J.
中科院分区：
文献类型：
--
作者：
Janssen, Rolf J. R. J.;Distelmaier, Felix;Nijtmans, Leo G. J.
影响线粒体氧化磷酸化系统的连续体基因综合征很少报道。在这里，我们描述了一个明显的线粒体脑肌病伴随着几个不寻常的功能，包括畸形和肝病，由5号染色体上的纯合三基因缺失引起的患者。该缺失包括NDUFAF 2、ERCC 8和NDUVL 7基因，分别编码复合物I组装因子2（也称为人B17.2L）、转录偶联核苷酸切除修复（TC-NER）机制的蛋白质和推定的极长链脂肪酸合成延长酶。对培养的皮肤成纤维细胞的详细评价揭示了复合物I组装紊乱、线粒体膜去极化、细胞NAD（P）H水平升高、超氧化物产生增加和TC-NER缺陷。在这些细胞中没有检测到VL 7 mRNA，也没有发现脂肪酸合成的改变，通过杆状病毒互补，我们能够恢复畸变，从而建立基因型和细胞生理表型之间的因果关系。这第一个染色体微缺失表明，除了线粒体基因的主要缺陷之外，其他基因也可能导致疾病表型，为与这些疾病相关的广泛临床症状提供了额外的解释。
Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.