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中国额颞叶痴呆的遗传和临床特征：TBK1 和 OPTN 突变的优势。

Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.

机构信息

Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.

Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

出版信息

Alzheimers Res Ther. 2024 Jun 13;16(1):127. doi: 10.1186/s13195-024-01493-w.

DOI:10.1186/s13195-024-01493-w
PMID:38872230
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11170894/
Abstract

BACKGROUND

Our study aims to evaluate the genetic and phenotypic spectrum of Frontotemporal dementia (FTD) gene variant carriers in Chinese populations, investigate mutation frequencies, and assess the functional properties of TBK1 and OPTN variants.

METHODS

Clinically diagnosed FTD patients underwent genetic analysis through exome sequencing, repeat-primed polymerase chain reaction, and Sanger sequencing. TBK1 and OPTN variants were biologically characterized in vitro using immunofluorescence, immunoprecipitation, and immunoblotting analysis. The frequencies of genes implicated in FTD in China were analyzed through a literature review and meta-analysis.

RESULTS

Of the 261 Chinese FTD patients, 61 (23.4%) carried potential causative variants in FTD-related genes, including MAPT (n = 17), TBK1 (n = 7), OPTN (n = 6), GRN (n = 6), ANXA11 (n = 4), CHMP2B (n = 3), C9orf72 GGGGCC repeats (n = 2), CYLD (n = 2), PRNP (n = 2), SQSTM1 (n = 2), TARDBP (n = 2), VCP (n = 1), CCNF (n = 1), CHCHD10 (n = 1), SIGMAR1 (n = 1), CHCHD2 (n = 1), FUS (n = 1), TMEM106B (n = 1), and UBQLN2 (n = 1). 29 variants can be considered novel, including the MAPT p.D54N, p.E342K, p.R221P, p.T263I, TBK1 p.E696G, p.I37T, p.E232Q, p.S398F, p.T78A, p.Q150P, p.W259fs, OPTN p.R144G, p.F475V, GRN p.V473fs, p.C307fs, p.R101fs, CHMP2B p.K6N, p.R186Q, ANXA11 p.Q155*, CYLD p.T157I, SQSTM1 p.S403A, UBQLN2 p.P509H, CCNF p.S160N, CHCHD10 p.A8T, SIGMAR1 p.S117L, CHCHD2 p.P53fs, FUS p.S235G & p.S236G, and TMEM106B p.L144V variants. Patients with TBK1 and OPTN variants presented with heterogeneous clinical phenotypes. Functional analysis demonstrated that TBK1 I37T and E232Q mutants showed decreased autophosphorylation, and the OPTN phosphorylation was reduced by the TBK1 I37T mutant. The OPTN-TBK1 complex formation was enhanced by the TBK1 E696G mutant, while OPTN R144G and F475V mutants exhibited reduced recruitment to autophagosomes compared to the wild-type. The overall frequency of TBK1 and OPTN in Chinese FTD patients was 2.0% and 0.3%, respectively.

CONCLUSIONS

Our study demonstrates the extensive genetic and phenotypic heterogeneity of Chinese FTD patients. TBK1 mutations are the second most frequent cause of clinical FTD after MAPT in the Chinese.

摘要

背景

本研究旨在评估中国人群中额颞叶痴呆（FTD）基因变异携带者的遗传和表型谱，调查突变频率，并评估 TBK1 和 OPTN 变异体的功能特性。

方法

通过外显子组测序、重复引物聚合酶链反应和 Sanger 测序对临床诊断为 FTD 的患者进行基因分析。使用免疫荧光、免疫沉淀和免疫印迹分析对 TBK1 和 OPTN 变体进行体外生物学特征分析。通过文献综述和荟萃分析分析中国与 FTD 相关的基因的频率。

结果

在 261 名中国 FTD 患者中，61 名（23.4%）携带 FTD 相关基因的潜在致病变异，包括 MAPT（n=17）、TBK1（n=7）、OPTN（n=6）、GRN（n=6）、ANXA11（n=4）、CHMP2B（n=3）、C9orf72 GGGGCC 重复序列（n=2）、CYLD（n=2）、PRNP（n=2）、SQSTM1（n=2）、TARDBP（n=2）、VCP（n=1）、CCNF（n=1）、CHCHD10（n=1）、SIGMAR1（n=1）、CHCHD2（n=1）、FUS（n=1）、TMEM106B（n=1）和 UBQLN2（n=1）。29 种变异可以被认为是新的，包括 MAPT p.D54N、p.E342K、p.R221P、p.T263I、TBK1 p.E696G、p.I37T、p.E232Q、p.S398F、p.T78A、p.Q150P、p.W259fs、OPTN p.R144G、p.F475V、GRN p.V473fs、p.C307fs、p.R101fs、CHMP2B p.K6N、p.R186Q、ANXA11 p.Q155*、CYLD p.T157I、SQSTM1 p.S403A、UBQLN2 p.P509H、CCNF p.S160N、CHCHD10 p.A8T、SIGMAR1 p.S117L、CHCHD2 p.P53fs、FUS p.S235G 和 p.S236G 以及 TMEM106B p.L144V 变异。携带 TBK1 和 OPTN 变异的患者表现出异质性的临床表型。功能分析表明，TBK1 I37T 和 E232Q 突变体的自体磷酸化减少，TBK1 I37T 突变体的 OPTN 磷酸化减少。TBK1 E696G 突变增强了 OPTN-TBK1 复合物的形成，而 OPTN R144G 和 F475V 突变体与野生型相比，招募到自噬体的能力降低。TBK1 和 OPTN 在中国 FTD 患者中的总体频率分别为 2.0%和 0.3%。

结论

本研究表明中国 FTD 患者具有广泛的遗传和表型异质性。TBK1 突变是继 MAPT 之后中国第二常见的临床 FTD 病因。

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