Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease
Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease
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DOI：
10.1073/pnas.1419581111
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发表时间：
2014-12-23
影响因子：
11.1
通讯作者：
Tekinay, Ayse B.
中科院分区：
文献类型：
--
作者：
Gulsuner, Hilal Unal;Gulsuner, Suleyman;Tekinay, Ayse B.
特发性震颤是人类最常见的运动障碍之一，并可能与实质性残疾有关。一些但不是所有患有特发性震颤的人都会出现帕金森病的症状，这些疾病之间的关系尚不清楚。在一个六代同堂的土耳其亲属与原发性震颤和帕金森病，我们进行了全外显子组测序和系谱分析，确定HTRA2 p.G399S的等位基因可能负责这两种情况。原发性震颤存在于该等位基因的杂合子或纯合子中。纯合子与震颤发病年龄早（P < 0.0001）、姿势性震颤更严重（P < 0.0001）和运动性震颤更严重（P = 0.0019）相关。纯合子，而不是杂合子，在中年时出现帕金森症状。在来自与该家族相同的安纳托利亚地区的人群对照中，HTRA2 p.G399S的频率为0.0027，略低于其他人群。HTRA2编码线粒体丝氨酸蛋白酶。HtrA2功能的丧失先前显示在运动神经元变性（mnd2）小鼠中导致帕金森病特征。HTRA2 p.G399S先前被证明会导致线粒体功能障碍、线粒体形态改变和蛋白酶活性降低，但HTRA2与帕金森病之间相关性的流行病学研究产生了相互矛盾的结果。我们的研究结果表明，在一些家庭中，HTRA2 p.G399S是负责遗传性特发性震颤和该等位基因的纯合子发展帕金森病。这一假说对理解原发性震颤的发病机制及其与帕金森病的关系具有重要意义。
Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p. G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p. G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.