An ANXA11 P93S variant dysregulates TDP‐43 and causes corticobasal syndrome

• DOI: 10.1002/alz.13915
• Publication Date: 2024-06-26T07:21:49Z
• Authors: Allison Snyder; Veronica H. Ryan; James Hawrot; Sydney Lawton; Daniel M. Ramos; Y. Andy Qi; Kory R. Johnson; Xylena Reed; Nicholas L. Johnson; Aaron W. Kollasch; Megan F. Duffy; Lawren VandeVrede; J. Nicholas Cochran; Bruce L. Miller; Camilo Toro; Bibiana Bielekova; Debora S. Marks; Jennifer S. Yokoyama; Justin Y. Kwan; Mark R. Cookson; Michael E. Ward
• Keywords: Male; 570; Annexins; TDP-43; Clinical Sciences; ANXA11; Clinical sciences; Neurodegenerative; Article; Rare Diseases; 616; Genetics; 2.1 Biological and endogenous factors; Humans; Aged; Neurons; Biomedical and Clinical Sciences; variant of uncertain significance; Amyotrophic Lateral Sclerosis; Neurosciences; corticobasal syndrome; Middle Aged; Brain Disorders; DNA-Binding Proteins; TDP‐43; Geriatrics; Frontotemporal Dementia; Neurological; Mutation; Biological psychology; Female; Research Article

Abstract INTRODUCTION Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity a novel VUS P93S in Annexin A11 (ANXA11) – an amyotrophic lateral sclerosis/frontotemporal dementia‐associated gene corticobasal syndrome kindred. Established ANXA11 mutations cause aggregation, altered lysosomal‐RNA granule co‐trafficking, and transactive response DNA binding protein 43 kDa (TDP‐43) mis‐localization. METHODS described clinical presentation explored phenotypic diversity variants. P93S's effect on function TDP‐43 biology was characterized induced pluripotent stem cell‐derived neurons alongside multiomic neuronal microglial profiling. RESULTS were linked to cases. led decreased lysosome colocalization, neuritic RNA, nuclear cryptic exon expression. Multiomic signatures implicated immune dysregulation interferon signaling pathways. DISCUSSION This study establishes pathogenicity, broadens spectrum mutations, underscores dysfunction pathophysiology, demonstrates potential cellular models determine variant Highlights is pathogenic variant. Corticobasal part spectrum. Hybridization chain reaction fluorescence situ hybridization (HCR FISH) new tool detection exons due TDP‐43‐related loss splicing regulation. Microglial related pathways are important drivers disease. Cellular powerful tools adjudicating variants significance.