Lee Sun Min, Yoon Soo Jin, Park Kyung Won, Kim Ahro, Kim Hee Jin, Jung Na-Yeon, Jang Hyemin, Seeley William W, Kim Young-Eun, Moon So Young, Kim Eun-Joo
Department of Neurology, Ajou University School of Medicine, Suwon, South Korea.
Department of Neurology, Daejeon Eulji Medical Center, Eulji University, Daejeon, South Korea.
Alzheimers Dement. 2025 Mar;21(3):e14566. doi: 10.1002/alz.14566.
Pathogenic variants of annexin A11 (ANXA11) have been identified in patients with amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). We explored ANXA11 pathogenic variants in a Korean FTD cohort to investigate the prevalence and the role of ANXA11 variation in FTD.
We used next-generation sequencing (NGS) to search for pathogenic variants in ANXA11 in two nationwide FTD cohorts in Korea.
We identified a pathogenic variant in ANXA11, c.119A > G (p.D40G), in six patients with semantic variant primary progressive aphasia (svPPA), representing 5.5% of the svPPA cohort (6/109), and representing 2.3% of the FTD cohort overall (6/259). Only one patient later developed features suggestive of ALS.
This study links a rare variant in ANXA11 to a sporadic clinical syndrome in which specific TAR DNA-binding protein-43 (TDP-43) forms an obligate co-fibril with annexin A11. The variant, p.D40G, lies within the N-terminal portion of annexin A11's TDP-43 type C interacting domain, suggesting that genetic variation in that region may promote co-fibrillization.
The pathogenic variant of annexin A11 (ANXA11I) is linked to frontotemporal dementia (FTD) syndrome. ANXA11 (p.D40G) may be one of the possible genetic causes of semantic variant primary progressive aphasia (svPPA). ANXA11 (p.D40G) may enhance heteromeric amyloid filaments of annexin A11 and TDP-43, promoting frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) type C.
在患有或未患有额颞叶痴呆（FTD）的肌萎缩侧索硬化症（ALS）患者中已鉴定出膜联蛋白A11（ANXA11）的致病变异。我们在一个韩国FTD队列中探索了ANXA11致病变异，以调查ANXA11变异在FTD中的患病率和作用。
我们使用下一代测序（NGS）在韩国两个全国性FTD队列中搜索ANXA11中的致病变异。
我们在6例语义变异型原发性进行性失语（svPPA）患者中鉴定出ANXA11中的一个致病变异，c.119A>G（p.D40G），占svPPA队列的5.5%（6/109），占整个FTD队列 的2.3%（6/259）。只有1例患者后来出现了提示ALS的特征。
本研究将ANXA11中的一种罕见变异与一种散发性临床综合征联系起来，在该综合征中，特定的TAR DNA结合蛋白43（TDP-43）与膜联蛋白A11形成一种必需的共原纤维。该变异p.D40G位于膜联蛋白A11的TDP-43 C型相互作用结构域的N端部分，表明该区域的基因变异可能促进共原纤维形成。
膜联蛋白A11（ANXA11）的致病变异与额颞叶痴呆（FTD）综合征有关。ANXA11（p.D40G）可能是语义变异型原发性进行性失语（svPPA）的可能遗传原因之一。ANXA11（p.D40G）可能增强膜联蛋白A11和TDP-43的异源淀粉样细丝，促进伴有TAR DNA结合蛋白43（TDP-43）包涵体的额颞叶变性（FTLD-TDP）C型。
