Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.
Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.
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DOI：
10.1002/ana.23829
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发表时间：
2013-04
影响因子：
11.2
通讯作者：
Klein C
中科院分区：
文献类型：
--
作者：
Lohmann K;Wilcox RA;Winkler S;Ramirez A;Rakovic A;Park JS;Arns B;Lohnau T;Groen J;Kasten M;Brüggemann N;Hagenah J;Schmidt A;Kaiser FJ;Kumar KR;Zschiedrich K;Alvarez-Fischer D;Altenmüller E;Ferbert A;Lang AE;Münchau A;Kostic V;Simonyan K;Agzarian M;Ozelius LJ;Langeveld AP;Sue CM;Tijssen MA;Klein C
进行了一项研究，以确定潜在的DYT 4肌张力障碍，一种显性遗传形式的痉挛性发声障碍结合其他局灶性或全身性肌张力障碍和特征性的面容和身体形态，在澳大利亚的家庭基因。对14个家系成员进行了全基因组连锁分析，随后对2个个体进行了基因组测序。索引患者进行了详细的神经系统随访检查，包括电生理研究和磁共振成像扫描。获得皮肤和嗅粘膜活检组织，并通过定量实时聚合酶链反应测定3种不同细胞类型中TUBB 4 mRNA的表达水平。在394名无关的肌张力障碍患者中筛查TUBB 4的所有外显子的突变。致病基因定位于染色体19p13.3-p13.2上的23 cM区域，标记D9 S427和D9 S1034处的最大多点LOD得分为5.338。基因组测序显示TUBB 4（微管蛋白β-4; Arg 2Gly）基因中的错义变体可能是疾病的原因。在394例不相关的肌张力障碍患者中进行TUBB 4测序，发现了一个节段性肌张力障碍伴痉挛性发声障碍家族性病例中的另一个错义变体（Ala 271 Thr）。mRNA表达研究表明，与对照组相比，来自杂合Arg 2Gly突变携带者的不同细胞类型中突变TUBB 4 mRNA的水平显著降低。TUBB 4的突变导致这个澳大利亚家族的DYT 4肌张力障碍，即所谓的耳语性发音障碍，TUBB 4的其他突变可能导致痉挛性发音障碍。鉴于TUBB 4是一种神经元表达的微管蛋白，我们的研究结果意味着微管功能异常是肌张力障碍病理生理学中的一种新机制。
A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.
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影响因子：
48
作者：
Djarmati, Ana;Schneider, Susanne A.;Klein, Christine
通讯作者：
Klein, Christine
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
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通讯作者：
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Klein, Christine
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Klein, Christine
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通讯作者：
Duman, Ronald S.