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Abstract：
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.
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.
摘要：
背景：我们的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变体的功能特性。
方法：临床诊断为FTD的患者通过外显子组测序进行遗传分析，重复引发的聚合酶链反应，还有Sanger测序.TBK1和OPTN变体在体外使用免疫荧光进行生物学表征，免疫沉淀,和免疫印迹分析。通过文献综述和荟萃分析分析了中国FTD基因的频率。
结果：在261名中国FTD患者中，61（23.4％）在FTD相关基因中携带潜在的致病变异，包括MAPT(n=17)，TBK1（n=7），OPTN（n=6），GRN(n=6),ANXA11（n=4），CHMP2B（n=3），C9orf72GGGGCC重复(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个变体可以被认为是新颖的，包括MAPTp.D54N，p.E342K,p.R221P,p.T263I,TBK1p.E696G,p.I37T,p.E232Q,p.S398F,p.T78A,p.Q150P,p.W259fs,OPTNp.R144G,p.F475V,GRNp.V473fs,p.C307fs,p.R101fs,CHMP2Bp.K6N,p.R186Q,ANXA11p.Q155*,CYLDp.T157I,SQSTM1p.S403A,UBQLN2p.P509H,CCNFp.S160N,CHCHCHD10p.A8T,SIGMAR1p.S117L,CHCHD2p.P53fs,FUSp.S235G和p.S236G,和TMEM106Bp.L144V变体。TBK1和OPTN变异的患者呈现异质性临床表型。功能分析显示TBK1I37T和E232Q突变体显示出降低的自磷酸化,TBK1I37T突变体减少了OPTN的磷酸化。TBK1E696G突变体增强了OPTN-TBK1复合物的形成，与野生型相比，OPTNR144G和F475V突变体显示出减少的自噬体募集。TBK1和OPTN在中国FTD患者中的总体频率分别为2.0%和0.3%,分别。
结论：我们的研究证明了中国FTD患者广泛的遗传和表型异质性。TBK1突变是中国人临床FTD仅次于MAPT的第二常见原因。
方法：临床诊断为FTD的患者通过外显子组测序进行遗传分析，重复引发的聚合酶链反应，还有Sanger测序.TBK1和OPTN变体在体外使用免疫荧光进行生物学表征，免疫沉淀,和免疫印迹分析。通过文献综述和荟萃分析分析了中国FTD基因的频率。
结果：在261名中国FTD患者中，61（23.4％）在FTD相关基因中携带潜在的致病变异，包括MAPT(n=17)，TBK1（n=7），OPTN（n=6），GRN(n=6),ANXA11（n=4），CHMP2B（n=3），C9orf72GGGGCC重复(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个变体可以被认为是新颖的，包括MAPTp.D54N，p.E342K,p.R221P,p.T263I,TBK1p.E696G,p.I37T,p.E232Q,p.S398F,p.T78A,p.Q150P,p.W259fs,OPTNp.R144G,p.F475V,GRNp.V473fs,p.C307fs,p.R101fs,CHMP2Bp.K6N,p.R186Q,ANXA11p.Q155*,CYLDp.T157I,SQSTM1p.S403A,UBQLN2p.P509H,CCNFp.S160N,CHCHCHD10p.A8T,SIGMAR1p.S117L,CHCHD2p.P53fs,FUSp.S235G和p.S236G,和TMEM106Bp.L144V变体。TBK1和OPTN变异的患者呈现异质性临床表型。功能分析显示TBK1I37T和E232Q突变体显示出降低的自磷酸化,TBK1I37T突变体减少了OPTN的磷酸化。TBK1E696G突变体增强了OPTN-TBK1复合物的形成，与野生型相比，OPTNR144G和F475V突变体显示出减少的自噬体募集。TBK1和OPTN在中国FTD患者中的总体频率分别为2.0%和0.3%,分别。
结论：我们的研究证明了中国FTD患者广泛的遗传和表型异质性。TBK1突变是中国人临床FTD仅次于MAPT的第二常见原因。
