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

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机构： [1]Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China. [2]Department of Biochem‑ istry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409‑3898, Japan. [3]Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Chengdu 610072, China. [4]The Experimental High School Attached to Beijing Normal University, Beijing 100032, China.

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关键词： Frontotemporal dementia Genetic spectrum TBK1 OPTN Autophagy

摘要：

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.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.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.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.© 2024. The Author(s).

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基金编号： no. 82271464] and [no. 82201573

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出版当年[2023]版：

大类 | 1 区

医学

小类 | 1 区临床神经病学 1 区神经科学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区临床神经病学 1 区神经科学

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出版当年[2022]版：

Q1 CLINICAL NEUROLOGY Q1 NEUROSCIENCES

最新[2023]版：

Q1 CLINICAL NEUROLOGY Q1 NEUROSCIENCES

影响因子： 8 最新[2023版] 8.3 最新五年平均 9 出版当年[2022版] 9.2 出版当年五年平均 8.831 出版前一年[2021版] 8 出版后一年[2023版]

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第一作者机构： [1]Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, China.

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

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