Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLD_M719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLD_M719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLD_M719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD’s interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

中文翻译：

---

CYLD是额颞叶痴呆-肌萎缩侧索硬化症的致病基因。

额颞叶痴呆和肌萎缩侧索硬化症是临床和病理上重叠的疾病，具有共同的遗传原因。我们之前在染色体 16p12.1-q12.2 上发现了一个具有全基因组显着联系的疾病基因座，该家族具有额颞叶痴呆和肌萎缩侧索硬化的常染色体显性遗传，并且在已知的肌萎缩侧索硬化或痴呆基因中没有突变。在这里，我们证明了在连锁区域内 CYLD (c.2155A> G, p.M719V) 中一种新的错义变体的分离是该家族疾病的遗传原因。来自两个CYLD的脑组织的免疫组织化学分析p.M719V 突变携带者表现出广泛的胶质细胞 CYLD 免疫反应性。_{用CYLD M719V}转染的原代小鼠神经元表现出 TDP-43 的细胞质定位增加和轴突缩短。CYLD编码赖氨酸 63 去泛素酶，CYLD 皮肤综合征是一种皮肤肿瘤疾病，由导致去泛素酶活性降低的突变引起。与导致 CYLD 皮肤综合征的突变相比，_{CYLD M719V}表现出相对于野生型酶显着增加的赖氨酸 63 去泛素酶活性（配对 Wilcoxon 符号秩检验P = 0.005）。_{CYLD M719V}的过表达在 HEK293 细胞中，导致细胞信号分子 NF-κB 的更有效抑制和自噬体与溶酶体融合的损害，这是自噬的关键过程。尽管CYLD突变似乎很少见，但 CYLD 与至少三种由额颞叶痴呆和/或肌萎缩侧索硬化基因（TBK1、OPTN和SQSTM1）编码的其他蛋白质的相互作用表明它可能在这些疾病的发病机制中发挥核心作用。几种额颞叶痴呆和肌萎缩侧索硬化基因的突变，包括TBK1、OPTN和SQSTM1，导致自噬功能丧失。我们在这里表明，增加的 CYLD 活性也会降低自噬功能，突出自噬调节在额颞叶痴呆和肌萎缩性侧索硬化发病机制中的重要性。