Departments of *Neurology ‡Ophthalmology, Institute of Clinical Medicine, University of Oulu †Clinical Research Center, Oulu University Hospital, Oulu, Finland §Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD ∥Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland ¶Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
Alzheimer Dis Assoc Disord. 2014 Apr-Jun;28(2):190-3. doi: 10.1097/WAD.0b013e318266fae5.
Frontotemporal lobar degeneration (FTLD) is a genetically heterogenous syndrome and has been associated most recently with a hexanucleotide repeat expansion within the C9ORF72 gene. Pathogenic TDP-43 gene (TARDBP) mutations have been identified in amyotrophic lateral sclerosis, but the role of TARDBP mutations in FTLD is more contradictory. To investigate the role of TARDBP mutations in a clinical series of Finnish FTLD patients, we sequenced TARDBP exons 1 to 6 in 77 FTLD patients. No evident pathogenic mutations were found. We identified a novel heterozygous c.876_878delCAG sequence variant in 2 related patients with behavioral variant frontotemporal dementia without amyotrophic lateral sclerosis. The variant is predicted to cause an amino acid deletion of serine at position 292 (p.Ser292del). However, p.Ser292del was also found in 1 healthy middle-aged control. Interestingly, both patients carried the C9ORF72 expansion. Therefore, the TARDBP variant p.Ser292del might be considered a rare polymorphism and the C9ORF72 repeat expansion the actual disease-causing mutation in the family. Our results suggest that TARDBP mutations are a rare cause of FTLD. However, the interaction of several genetic factors needs to be taken into account when investigating neurodegenerative diseases.
额颞叶变性（FTLD）是一种遗传异质性综合征，最近与 C9ORF72 基因内的六核苷酸重复扩展有关。致病性 TDP-43 基因（TARDBP）突变已在肌萎缩侧索硬化症中被鉴定出来，但 TARDBP 突变在 FTLD 中的作用更具争议性。为了研究 TARDBP 突变在芬兰 FTLD 患者临床系列中的作用，我们对 77 名 FTLD 患者的 TARDBP 外显子 1 到 6 进行了测序。未发现明显的致病性突变。我们在 2 名无肌萎缩侧索硬化症的行为变异额颞叶痴呆相关患者中发现了一种新的杂合 c.876_878delCAG 序列变异。该变体预计会导致第 292 位丝氨酸（p.Ser292del）的氨基酸缺失。然而，在 1 名健康的中年对照中也发现了 p.Ser292del。有趣的是，这两名患者都携带 C9ORF72 扩展。因此，TARDBP 变体 p.Ser292del 可能被认为是一种罕见的多态性，而 C9ORF72 重复扩展是该家族中的实际致病突变。我们的结果表明，TARDBP 突变是 FTLD 的罕见原因。然而，在研究神经退行性疾病时，需要考虑几个遗传因素的相互作用。
