PDF(Pubmed)
Abstract：
Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.
We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S\'s effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.
ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.
This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.
ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.
We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S\'s effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.
ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.
This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.
ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.
摘要：
背景：不确定意义的变体（VUS）随着负担得起的基因检测而激增，对确定致病性构成挑战。我们检查了一种新型VUSP93S在一种皮质基底综合征中膜联蛋白A11（ANXA11）中的致病性-一种肌萎缩性侧索硬化症/额颞叶痴呆相关基因。已建立的ANXA11突变导致ANXA11聚集，改变的溶酶体-RNA颗粒共同运输，和43kDa（TDP-43）错误定位的反式反应DNA结合蛋白。
方法：我们描述了ANXA11变异体的临床表现并探索了其表型多样性。P93S对ANXA11功能和TDP-43生物学的影响在诱导的多能干细胞衍生的神经元以及多体神经元和小胶质细胞谱分析中表征。
结果：ANXA11突变与皮质基底综合征病例相关。P93S导致溶酶体共定位减少，神经RNA，和细胞核的TDP-43具有隐蔽的外显子表达。多组学小胶质细胞特征涉及免疫失调和干扰素信号通路。
结论：本研究建立了ANXA11P93S致病性，拓宽ANXA11突变的表型谱，强调ANXA11病理生理学中的神经元和小胶质细胞功能障碍，并证明了细胞模型确定变异致病性的潜力。
结论：ANXA11P93S是一种致病变种。皮质基底综合征是ANXA11表型谱的一部分。杂交链反应荧光原位杂交（HCRFISH）是一种新的工具，用于检测由于TDP-43相关的剪接调节丢失而导致的隐蔽外显子。小胶质细胞ANXA11和相关的免疫途径是疾病的重要驱动因素。细胞模型是裁定具有不确定意义的变体的强大工具。
方法：我们描述了ANXA11变异体的临床表现并探索了其表型多样性。P93S对ANXA11功能和TDP-43生物学的影响在诱导的多能干细胞衍生的神经元以及多体神经元和小胶质细胞谱分析中表征。
结果：ANXA11突变与皮质基底综合征病例相关。P93S导致溶酶体共定位减少，神经RNA，和细胞核的TDP-43具有隐蔽的外显子表达。多组学小胶质细胞特征涉及免疫失调和干扰素信号通路。
结论：本研究建立了ANXA11P93S致病性，拓宽ANXA11突变的表型谱，强调ANXA11病理生理学中的神经元和小胶质细胞功能障碍，并证明了细胞模型确定变异致病性的潜力。
结论：ANXA11P93S是一种致病变种。皮质基底综合征是ANXA11表型谱的一部分。杂交链反应荧光原位杂交（HCRFISH）是一种新的工具，用于检测由于TDP-43相关的剪接调节丢失而导致的隐蔽外显子。小胶质细胞ANXA11和相关的免疫途径是疾病的重要驱动因素。细胞模型是裁定具有不确定意义的变体的强大工具。
