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湘雅医院发现舞蹈手足徐动症致病基因PRRT2

2012/01/06 来源:岛民网
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中南大学湘雅医院对外透露,他们与合作者在国际上首次发现和克隆了“舞蹈手足徐动症”的第一个致病基因PRRT2。研究成果2011年11月26日在神经病学领域国际权威杂志《Brain》期刊网站上率先发表。

中南大学湘雅医院对外透露,他们与合作者在国际上首次发现和克隆了“舞蹈手足徐动症”的第一个致病基因PRRT2。研究成果2011年11月26日在神经病学领域国际权威杂志《Brain》期刊网站上率先发表。

12岁的学生李敏(化名)最近被老师和同学指责上课搞“恶作剧”:回答问题时双手不自主的“舞蹈”,或“挤眉弄眼”地搞怪。他还时而感觉到双脚僵硬经常摔倒,几次险些出了车祸。

经查明,李敏患有发作性运动诱发性运动障碍(PKD),又称发作性运动诱发的舞蹈手足徐动症。这一类以发作性肢体不自主运动和躯体姿态异常的发生与遗传因素有关。李敏家族中的父亲、叔叔、奶奶等四代人、超10人均患上了这个怪病。另有医学专家认为脑血管病、代谢紊乱、脑外伤等也可能诱发此病。

湘雅医院神经内科唐北沙教授领衔的团队与上海交通大学医学院附属瑞金医院神经内科、中山大学附属第一医院神经内科、中南大学医学遗传学国家重点实验室、深圳华大基因科技有限公司等多家单位合作,通过对PKD深入研究,发现在人脑高表达的PRRT2(富脯氨酸跨膜蛋白2)基因突变后,可导致该病发生,并在国际上首次研究发现PRRT2基因是PKD的第一个致病基因。

参与研究的王俊岭博士说,PKD已有较多的病例报道,目前定位了2个致病基因区间,但至今未能克隆出致病基因。


Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias

Jun-Ling Wang, Li Cao, Xun-Hua Li, Zheng-Mao Hu, Jia-Da Li, Jian-Guo Zhang, Yu Liang, San-A, Nan Li, Su-Qin Chen, Ji-Feng Guo, Hong Jiang, Lu Shen, Lan Zheng, Xiao Mao, Wei-Qian Yan, Ying Zhou, Yu-Ting Shi, San-Xi Ai, Mei-Zhi Dai, Peng Zhang, Kun Xia, Sheng-Di Chen and Bei-Sha Tang

Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1–q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.

文献链接:http://brain.oxfordjournals.org/content/134/12/3493.full

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