Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia
Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia
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DOI：
10.1016/j.neurobiolaging.2010.12.013
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Bruni, Amalia C.
中科院分区：
文献类型：
--
作者：
Anfossi, Maria;Vuono, Romina;Bruni, Amalia C.
内含子MAPT突变改变外显子10剪接主要导致4Rtau的增加。本研究的目的是报告一个明显散发的早发性额颞叶痴呆（ETD）病例的临床、遗传和神经病理学数据，该病例与两个新的内含子MAPT基因突变IVS10+4A > C和IVS9-15T > C相关，这些突变增加了3Rtau。使用的方法和对象是临床、神经放射学和神经病理学检查；MAPT、PGRN等相关基因的分子遗传学研究。外显子10剪接测试与minigene结构。免疫组织化学检测Tau沉积。免疫印迹法研究萨科齐不溶性和可溶性tau蛋白。两种新的MAPT突变IVS10+4A > C和IVS9-15T > C由未受影响的父母传播。对minigenes和脑组织的半定量逆转录聚合酶链反应（RT-PCR）分析显示，这两种突变都导致患者仅缺乏外显子10的tau mRNA（信使核糖核酸）转录物增加。患者大脑的免疫组织化学和免疫印迹显示，tau沉积物主要由3Rtau亚型组成，并以较短的3Rtau亚型为主。患者增加3Rtau的复合杂合性似乎是导致该疾病的原因，并且进一步表明散发病例可能是由基因突变引起的。(C) 2011爱思唯尔公司版权所有。
Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropatholoical data of an apparently sporadic early onset frontotemporal dementia (ETD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR,) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations. (C) 2011 Elsevier Inc. All rights reserved.