Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia
Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia
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DOI：
10.1016/j.neurobiolaging.2022.12.009
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发表时间：
2023-01-25
影响因子：
4.2
通讯作者：
Wu，Zhi-Ying
中科院分区：
文献类型：
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作者：
Cheng，Hong-Rong;Lin，Rong-Rong;Wu，Zhi-Ying
额颞叶痴呆（FTD）是仅次于阿尔茨海默病的第二大痴呆原因，其特征是行为、个性和语言的明显变化。本研究对29例无亲缘关系的FTD患者进行了全外显子组测序和重复引物PCR分析。因此，鉴定出2个已知的致病变异（MAPT: p.P301L;TBK1: p.p i450kfs）和4个新的变异（MAPT: p.p r406q, p.p d430h, p.p a330d;GRN: c.p 350- 2a >G）。功能分析结果显示，在表达p.R406Q和p.D430H tau的细胞中，磷酸化的tau水平高于表达野生型tau的细胞，特别是在Thr205、Thr231和Ser396磷酸化表位上。此外，maptimp . r406q和p.D430H变异配对了tau与微管结合的能力，并增加了tau的自聚集。此外，我们发现c.350-2A >g变异导致外显子5跳变。我们的结果显示p.R406Q、p.D430H和c.350-2A >g变异被归为致病性。最后，我们总结了东亚人群中携带致病变异maptin的患者的临床特征。我们的研究结果扩大了FTD与maptandgrn变体的遗传谱。
Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer's disease, characterized by distinct changes in behavior, personality, and language. Our study performed whole exome sequencing and repeat-primed PCR analysis in 29 unrelated FTD patients. Consequently, 2 known pathogenic variants (MAPT: p.P301L;TBK1: p.I450Kfs), and 4 novel variants (MAPT: p.R406Q, p.D430H, p.A330D;GRN: c.350-2A>G) were identified. The functional analysis results showed that phosphorylated tau levels were higher in cells expressing p.R406Q and p.D430H tau than those expressing wild-type tau, especially at the Thr205, Thr231, and Ser396 phosphorylation epitopes. Besides, the p.R406Q and p.D430H variants ofMAPTimpaired the ability of tau to bind to the microtubules and increased tau self-aggregation. Furthermore, we found that the c.350-2A>G variant caused exon 5 skipping. Our results showed that p.R406Q, p.D430H, and c.350-2A>G variants were classified as pathogenic. Finally, we summarized the clinical characterization of patients carrying pathogenic variants ofMAPTin the East Asia populations. Our results broaden the genetic spectrum of FTD withMAPTandGRNvariants.