Naïmi Mourad, Bannwarth Sylvie, Procaccio Vincent, Pouget Jean, Desnuelle Claude, Pellissier Jean-François, Rötig Agnes, Munnich Arnold, Calvas Patrick, Richelme Christian, Jonveaux Philippe, Castelnovo Giovanni, Simon Mariella, Clanet Michel, Wallace Douglas, Paquis-Flucklinger Véronique
Department of Medical Genetics, Archet 2 Hospital, CHU Nice, France.
Eur J Hum Genet. 2006 Aug;14(8):917-22. doi: 10.1038/sj.ejhg.5201627. Epub 2006 Apr 26.
ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.
ANT1、TWINKLE和POLG基因影响线粒体DNA（mtDNA）稳定性，并与常染色体显性进行性眼外肌麻痹（PEO）有关，而POLG中的突变会导致多种临床表现，包括常染色体隐性PEO、感觉性共济失调神经病、构音障碍和眼肌麻痹（SANDO）、脊髓小脑共济失调和癫痫（SCAE）或阿尔珀斯综合征。在本研究中，我们使用基于变性高效液相色谱（dHPLC）的方法，报告了15例无亲缘关系患者的ANT1、TWINKLE和POLG基因的突变分析。这一系列患者说明了与mtDNA稳定性缺陷相关的大量临床表现，从孤立的良性PEO到致命的阿尔珀斯综合征。在15例患者中的6例（40%）共鉴定出7种不同的突变。在POLG中发现了6种不同的隐性突变，在TWINKLE中发现1种，而在ANT1中未发现突变。在POLG突变中，有3种是新的，包括2种错义突变和1种移码突变。还鉴定出17种中性变化和多态性，包括4种新的中性多态性。总体而言，本研究说明了与mtDNA稳定性缺陷相关的表型变异性，增加了POLG变异的突变谱，并为ANT1、TWINKLE和POLG突变筛查提供了一种高效可靠的检测方法。
