A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts
A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts
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DOI：
10.1016/j.neurobiolaging.2012.10.009
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发表时间：
2013-06-01
影响因子：
4.2
通讯作者：
Weishaupt, Jochen H.
中科院分区：
文献类型：
--
作者：
Ingre, Caroline;Landers, John E.;Weishaupt, Jochen H.
Profilin 1是肌动蛋白动力学的中心调节因子。基因谱1 （PFN1）的突变最近被证明是肌萎缩性侧索硬化症（ALS）亚群的原因。在这里，我们对美国、北欧和德国的家族性和散发性ALS和额颞叶痴呆（FTLD）患者进行了PFN1突变的大筛选，以进一步了解该基因在完整的ALS/FTLD连续体中的谱和致病相关性。对来自德国、北欧国家和美国的112例家族性和260例散发性ALS病例和16例ALS/FTLD病例进行了PFN1突变筛查。研究了携带PFN1突变的患者的表型。在一个德国ALS家族中，我们发现了新的杂合PFN1突变p.s thr109met，这在对照组中是不存在的。这种新的突变消除了profil1中的一个磷酸化位点。最近描述的p.Gln117Gly序列变异是在另一位来自美国的家族性ALS患者中发现的。PFN1突变的ALS患者表现为脊髓性运动神经元疾病，但没有明显的认知损害。PFN1突变在运动神经元疾病和痴呆患者以及仅FTLD患者中不存在。我们提供了进一步的证据，证明PFN1突变可以导致ALS作为孟德尔显性性状。迄今为止报道的携带PFN1突变的患者代表了ALS- ftld谱系的“经典”ALS末端。新的p.s thr109met突变提供了额外的原理证明，即参与细胞骨架动力学调节的突变蛋白可以导致运动神经元变性。此外，这种新的突变表明，通过磷酸化profilin 1对肌动蛋白聚合进行微调可能是运动神经元存活所必需的。(C) 2013爱思唯尔公司版权所有。
Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the "classic" ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival. (C) 2013 Elsevier Inc. All rights reserved.