Taub Institute and Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, USA.
Neurobiol Aging. 2012 May;33(5):1016.e9-17. doi: 10.1016/j.neurobiolaging.2011.08.004. Epub 2011 Sep 23.
This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.
本研究旨在评估 FUS 和 TDP-43 基因的遗传变异性，这些基因主要与肌萎缩侧索硬化症（ALS）相关，在被诊断为额颞叶变性（FTLD）和皮质基底节综合征（CBS）的患者中。我们对 228 名患者的 DNA 进行了 FUS 和 TDP-43 基因的所有外显子和侧翼内含子筛选。我们在一名行为变异额颞叶痴呆（bvFTD）患者中发现了 FUS 的 2 个新的杂合错义突变：P106L（g.22508384C>T）和几个行为变异额颞叶痴呆家系成员中的 Q179H。我们还在一名 CBS 患者中发现了 TDP-43 的 N267S 突变，该突变先前仅在 1 个 ALS 家族和 1 个 FTD 患者中报道过。此外，我们在 FUS 的外显子 5 中发现了 2 个先前报道的杂合插入和缺失突变；FTD 患者中的 Gly174-Gly175delGG（g.4180-4185delGAGGTG）和 CBS 患者中的 Gly175-Gly176insGG（g.4185-4186insGAGGTG）。最重要的是，我们在神经正常的对照中也发现了一系列 FUS 变体。总之，我们报告称，FUS 和 TDP-43 的遗传变异性涵盖了广泛的表型（包括 ALS、FTD 和 CBS），并且在神经正常的对照中，FUS 基因存在大量的遗传变异性。
