Mitochondrial DNA polymerase W748S mutation:: A common cause of autosomal recessive ataxia with ancient European origin
Mitochondrial DNA polymerase W748S mutation:: A common cause of autosomal recessive ataxia with ancient European origin
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DOI：
10.1086/444548
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发表时间：
2005-09-01
影响因子：
9.8
通讯作者：
Suomalainen, A
中科院分区：
文献类型：
--
作者：
Hakonen, AH;Heiskanen, S;Suomalainen, A
线粒体DNA聚合酶g(Polg)催化亚单位的突变被发现是神经系统疾病的重要原因。最近，我们和合作者报道了一种新的神经退行性疾病，伴有常染色体隐性遗传性共济失调，患者为POLG中两个氨基酸变化的纯合子：顺式基因W748S和E1143G。在这里，我们研究了该等位基因的频率，发现它是芬兰遗传性共济失调最常见的遗传原因之一。我们鉴定了来自15个芬兰家庭的27例线粒体隐性共济失调综合征(MIRAS)患者，其携带者频率在普通人群中为1：125。由于突变对W748S+E1143G也在欧洲患者中被描述，我们检测了13名带有W748S突变的非芬兰、欧洲患者的单倍型。单倍型分析显示，在来自芬兰、挪威、英国和比利时的患者中，所有携带这两种变化的染色体都来自一个共同的古代创始人。在芬兰和挪威，可以识别出核心单倍型之外的长的、常见的北方单倍型。尽管有相同的纯合子突变，但这种成人或青少年发病的芬兰患者具有令人惊讶的不同表型，尽管具有一系列特征，包括共济失调、周围神经病、构音障碍、轻度认知障碍、不自主运动、精神症状和癫痫发作。芬兰的高载频，挪威的高患者数量，以及古老的欧洲创始人染色体表明，这种新发现的共济失调应该被考虑在进行性共济失调综合征的一线鉴别诊断中。
Mutations in the catalytic subunit of the mitochondrial DNA polymerase g ( POLG) have been found to be an important cause of neurological disease. Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G. Here, we studied the frequency of this allele and found it to be among the most common genetic causes of inherited ataxia in Finland. We identified 27 patients with mitochondrial recessive ataxia syndrome ( MIRAS) from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, we examined the haplotypes of 13 non-Finnish, European patients with the W748S mutation. Haplotype analysis revealed that all the chromosomes carrying these two changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common, northern haplotypes, outside the core haplotype, could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult-or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicate that this newly identified ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.