Department of Neurology, Laboratory of Neurodegenerative Disorders, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Neurology, Laboratory of Neurodegenerative Disorders, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Neurobiol Dis. 2022 Dec;175:105907. doi: 10.1016/j.nbd.2022.105907. Epub 2022 Oct 21.
Variants in the annexin A11 gene (ANXA11) have been reported to be associated with amyotrophic lateral sclerosis (ALS). These variants may be involved in the pathogenesis of ALS by causing defects in intracellular protein trafficking. However, the genetic spectrum and clinical characteristics of ALS patients with ANXA11 variants are largely unknown.
Genetic analysis was performed on 1587 Chinese patients with ALS. Eight software packages were used to predict the deleteriousness of missense variants. In addition, we searched PubMed, Embase, and Web of Science for relevant literature and meta-analysed variant frequencies.
In our ALS cohort, we identified 20 non-synonymous variants in 29 ALS patients, including one stop-gain, one frameshift, and 18 rare missense variants with seven predicted pathogenic variants. In a literature review of 11 reported studies that included 69 patients, 37 ANXA11 variants were reported, with a frequency of 1.7%, which was similar to that in our cohort (1.8%). Both our cohort and previous reports showed that ANXA11 carriers were more commonly males than females (12/17 vs. 19/31). Patients carrying ANXA11 variants affecting the C-terminal of the protein had earlier disease onset and shorter survival times than those carrying variants affecting the N-terminal. We found a relatively longer median survival time than that previously reported (53.6 months vs. 46.0 months). Additionally, Caucasian ANXA11 carriers were more likely to have cognitive impairment, typically frontotemporal dementia (FTD) than their Asian counterparts (20.0% vs. 14.3%). While more than half of the patients in our cohort had cognitive impairment, none had FTD.
In our and previously published cases, ALS-associated ANXA11 variants predominantly affected the N- and C-terminal conserved domains. ANXA11 variant carriers are typically male and cognitively impaired. Our study extends the genotypic and phenotypic spectra of ALS patients with ANXA11 variants. Further expansion of the sample size is needed to analyse the clinical and non-motor symptom characteristics of patients and to deepen the understanding of the pathogenesis of ANXA11-associated ALS.
已有报道称，膜联蛋白 A11 基因 (ANXA11) 的变异与肌萎缩侧索硬化症 (ALS) 有关。这些变异可能通过导致细胞内蛋白运输缺陷而参与 ALS 的发病机制。然而，携带 ANXA11 变异的 ALS 患者的遗传谱和临床特征在很大程度上尚不清楚。
对 1587 例中国 ALS 患者进行基因分析。使用八种软件包预测错义变异的有害性。此外，我们还在 PubMed、Embase 和 Web of Science 上检索相关文献并进行了变异频率的荟萃分析。
在我们的 ALS 队列中，在 29 名 ALS 患者中发现了 20 个非同义变异，包括一个无义突变、一个移码突变和 18 个罕见的错义变异，其中有 7 个预测为致病性变异。在对 11 项已发表研究的文献综述中，包括 69 名患者，共报道了 37 个 ANXA11 变异，频率为 1.7%，与我们的队列相似（1.8%）。我们的队列和以前的报告都表明，携带 ANXA11 变异的患者比女性更常见（12/17 比 19/31）。携带影响蛋白 C 端的 ANXA11 变异的患者比携带影响蛋白 N 端的患者发病更早，生存时间更短。我们发现的中位生存时间比以前报道的要长（53.6 个月比 46.0 个月）。此外，白种人携带 ANXA11 变异的患者比亚洲人更有可能出现认知障碍，通常是额颞叶痴呆 (FTD)（20.0%比 14.3%）。虽然我们队列中的大多数患者都有认知障碍，但没有人患有 FTD。
在我们和以前发表的病例中，与 ALS 相关的 ANXA11 变异主要影响 N 端和 C 端保守结构域。携带 ANXA11 变异的患者通常为男性且存在认知障碍。我们的研究扩展了携带 ANXA11 变异的 ALS 患者的基因型和表型谱。需要进一步扩大样本量来分析患者的临床和非运动症状特征，并加深对 ANXA11 相关 ALS 发病机制的理解。
