ArticleAlzheimer's research & therapy2024
Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.
Article in Alzheimer's research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed.
- Review
- Annexin A11 and TDP-43: core players in neurodegeneration.Acta neuropathologica · 2026Review
- Short tandem repeat expansions in patients with neurodegenerative dementia.EBioMedicine · 2026Article
- Physiological and pathological roles of ANXA11: a multifunctional regulator in neurodegeneration and other disorders.Cell communication and signaling : CCS · 2026Review
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.Acta neuropathologica · 2025Article
- Analyses of NOTCH3 variants in Chinese patients with clinically diagnosed Alzheimer's disease and frontotemporal dementia.Alzheimer's research & therapy · 2025Article
- Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort.Journal of neurology · 2025Article
- ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia.European journal of neurology · 2025Article
- Role of the mitochondrial regulatory factor CHCHD2 in neurodegenerative diseases.Frontiers in neuroscience · 2025Review
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Abstract
backgroundOur 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.
methodsClinically 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.
resultsOf 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.
conclusionsOur 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.
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