TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.
TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.
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DOI：
10.1007/s00401-009-0571-7
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发表时间：
2009-11
影响因子：
12.7
通讯作者：
Cairns NJ
中科院分区：
文献类型：
--
作者：
Gitcho MA;Bigio EH;Mishra M;Johnson N;Weintraub S;Mesulam M;Rademakers R;Chakraverty S;Cruchaga C;Morris JC;Goate AM;Cairns NJ
编码TDP-43基因TARDBP的致病突变已在家族性肌萎缩侧索硬化症(FALS)中被报道，最近，在包括ALS和额颞叶变性(FTLD)在内的临床表型不同的家族中也有报道。在我们之前的研究中，测序分析在一个bvFTD和ALS家系的两个患病成员和一个无关的临床评估的FALS病例中发现了TARDBP基因3‘-非翻译区(3’-UTR)的一个变异。自那项研究以来，脑组织已经可以获得，并在尸检中证实了先证者的FTLD-TDP和bvFTD-ALS家族的兄弟的ALS，这里报告了这两个病例的神经病理。在982例对照组(1,964个等位基因)中未发现3‘-UTR变异体。为了确定该变异体的功能意义，我们进行了定量基因表达分析。等位基因特异性扩增显示疾病特异性等位基因表达显著增加22%(P<；0.05)，总TARDBP mRNA增加两倍。在一个具有临床bvFTD和ALS的家系中分离出这种变异，增加了以前与TARDBP变异相关的临床表型谱。总之，TARDBP变异可能导致临床和神经病理不同的表型，这种表型与一种称为TDP-43蛋白病的常见分子病理相关联。
Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.
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影响因子：
64.8
作者：
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通讯作者：
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通讯作者：
Mackenzie, Ian R. A.
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作者：
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通讯作者：
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