Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study
Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study
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DOI：
10.1016/s1474-4422(09)70083-3
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发表时间：
2009-05-01
期刊：
影响因子：
48
通讯作者：
Klein, Christine
中科院分区：
文献类型：
--
作者：
Djarmati, Ana;Schneider, Susanne A.;Klein, Christine
背景DYT 6是一种原发性、早发性扭转性肌张力障碍;然而，与DYT 1肌张力障碍不同，DYT 6肌张力障碍的症状经常累及颅颈区。最近，编码THAP的基因THAP 1中的两个突变方法我们通过序列分析和实时定量聚合酶链反应（PCR）在160例发病年龄较早的欧洲血统白色肌张力障碍患者（n=64）中筛选THAP 1，全身性肌张力障碍（n=35），肌张力障碍阳性家族史（n=56），或面部或喉部肌张力障碍。另外160名患有造口障碍的患者被筛选出THAP 1中报告的和新的变体。280神经健康对照筛选新发现的和以前报道的变化THAP 1和这些和额外的75个控制进行了筛选一个罕见的非编码mutation.Findings我们确定了两个突变THAP 1（388_389delTC和474 delA），分别在两个（1%）德国患者的160例肌张力障碍。这两个突变携带者都有喉肌张力障碍，从儿童时期开始，都发展为全身性肌张力障碍。因此，三名早发性全身性肌张力障碍伴口延髓受累的患者中有两名存在THAP 1突变。其中一名确诊的DYT 6肌张力障碍患者有两名家族成员，他们也携带相同的突变，具有微妙的运动体征。在320名患者中的20名和355名对照中的7名中发现了5'非翻译区中的罕见置换（-236_235GA -> TT）（p=0.0054）。解释虽然THAP 1中的突变在具有不同但主要是局灶性形式的肌张力障碍的患者中可能仅具有次要作用，但它们似乎确实与具有痉挛性发声障碍的早发性全身性肌张力障碍相关。这种症状的组合可能是DYT 6肌张力障碍的特征，并可能有助于DYT 1，DYT 4，DYT 12和DM 7肌张力障碍的鉴别诊断。除了已确定的突变外，THAP 1中罕见的非编码取代可能会增加肌张力障碍的风险。
Background DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two mutations in THAP1, the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia.Methods We screened THAP1 by sequence analysis and quantitative real-time polymerase chain reaction (PCR) in 160 white patients of European ancestry who had dystonia with an early age at onset (n=64), generalised dystonia (n=35), a positive family history of dystonia (n=56), or facial or laryngeal dystonia. Another 160 patients with dystoma were screened for reported and novel variants in THAP1. 280 neurologically healthy controls were screened for the newly identified and previously reported changes in THAP1 and these and an additional 75 controls were screened for a rare non-coding mutation.Findings We identified two mutations in THAP1 (388_389delTC and 474delA), respectively, in two (1%) German patients from the 160 patients with dystonia. Both mutation carriers had laryngeal dystonia that started in childhood and both went on to develop generalised dystonia. Thus, two of three patients with early-onset generalised dystonia with orobulbar involvement had mutations in THAP1. One of the identified patients with DYT6 dystonia had two family members with subtle motor signs who also carried the same mutation. A rare substitution in the 5' untranslated region (-236_235GA -> TT) was found in 20 of 320 patients and in seven of 355 controls (p=0.0054).Interpretation Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. This combination of symptoms might be a characteristic feature of DYT6 dystonia and could be useful in the differential diagnosis of DYT1, DYT4, DYT12, and DM7 dystonia. In addition to the identified mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia.