Haut Sandrine, de Villemeur Thierry Billette, Brivet Michèle, Guiochon-Mantel Anne, Boutron Audrey, Rustin Pierre, Legrand Alain, Slama Abdelhamid
Laboratoire de Biochimie, AP-HP Hôpital de Bicêtre, Paris, France.
Eur J Hum Genet. 2004 Mar;12(3):220-4. doi: 10.1038/sj.ejhg.5201132.
We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.
我们报告了一名患有严重生长发育迟缓及胰岛素样生长因子1（IgF1）缺乏症的患者，怀疑其存在线粒体异常。在血液淋巴细胞和皮肤成纤维细胞中发现了孤立的线粒体呼吸链复合物III缺乏症。对细胞色素b进行序列分析，细胞色素b是复合物III中唯一由线粒体DNA编码的亚基，结果显示存在纯合的G15498A突变，导致一个高度保守的氨基酸（甘氨酸251）被天冬氨酸取代。在从母亲及其兄弟身上采集的所有检测组织（淋巴细胞、成纤维细胞、发根和颊细胞）中均发现该突变为纯合子。在这些细胞中也证实存在复合物III缺乏症。然而，母亲和她的兄弟没有症状。在之前报道的一个病例中，该突变被认为是一种导致心肌病的突变，并且最近在酵母中证实了其致病性。然而，它似乎不符合线粒体DNA突变致病性的经典标准，尤其是异质性状态，并且在未受影响的亲属中虽然存在，但临床上没有表现。我们认为其他因素导致了G15498A线粒体DNA突变的临床变异性表达。
