Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.
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DOI：
10.1002/humu.20824
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发表时间：
2008-09
期刊：
影响因子：
3.9
通讯作者：
Copeland, William C.
中科院分区：
文献类型：
--
作者：
Wong, Lee-Jun C.;Naviaux, Robert K.;Brunetti-Pierri, Nicola;Zhang, Qing;Schmitt, Eric S.;Truong, Cavatina;Milone, Margherita;Cohen, Bruce H.;Wical, Beverly;Ganesh, Jaya;Basinger, Alice A.;Burton, Barbara K.;Swoboda, Kathryn;Gilbert, Donald L.;Vanderver, Adeline;Saneto, Russell P.;Maranda, Bruno;Arnold, Georgianne;Abdenur, Jose E.;Waters, Paula J.;Copeland, William C.
POLG基因突变已成为儿童和成人遗传性线粒体疾病的最常见原因之一。它们负责神经退行性疾病的至少6种主要表型的异质组，包括：1）儿童期肌脑肝病谱系障碍（MCHS），2）Alpers综合征，3）共济失调神经病谱系（ANS）障碍，4）肌阵挛癫痫肌病感觉性共济失调（MEMSA），5）常染色体隐性进行性外眼肌麻痹（arPEO），（6）常染色体显性进行性外眼肌麻痹（adPEO）。由于临床异质性、症状的时间依赖性演变、重叠表型和肌肉病理学发现的不一致性，明确诊断依赖于有害突变的分子发现。我们对约350例表现出与POLG相关线粒体疾病表型一致的患者的外显子和侧翼内含子区进行了测序，并在61例（17%）中发现了信息突变。在31例常染色体隐性遗传POLG相关疾病的无关指数患者中发现了两个突变等位基因。其中Alpers综合征20例（67%），arPEO 4例（13%），ANS 3例（10%）。此外，还发现30例患者携带一个POLG等位基因，共发现25个新的突变，包括6个无效突变。我们描述了预测的结构/功能和临床的重要性，以前未报告的错义变异，并讨论其致病的可能性。总之，序列分析允许鉴定导致POLG相关疾病的突变，并且在大多数常染色体隐性病例中，发现两个突变等位基因处于反式，发现有害突变可以提供疾病的明确诊断。
Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.
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影响因子：
14.5
作者：
Ferrari, G;Lamantea, E;Zeviani, M
通讯作者：
Zeviani, M
影响因子：
11.2
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影响因子：
2.8
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Milone, Margherita;Brunetti-Pierri, Nicola;Wong, Lee-Jun C.
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Wong, Lee-Jun C.
影响因子：
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作者：
Barthélémy, C;de Baulny, HO;Lombès, A
通讯作者：
Lombès, A
影响因子：
3.6
作者：
de Vries, Maaike C.;Rodenburg, Richard J.;Smeitink, Jan A. M.
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Smeitink, Jan A. M.