ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2024
An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- Frontotemporal Lobar Degeneration-TDP Type C With Striatal Glial Cytoplasmic Inclusions and Motor Neuron Degeneration.Neuropathology and applied neurobiology · 2026Article
- The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.Developmental cell · 2026Article
- Annexin A11 and TDP-43: core players in neurodegeneration.Acta neuropathologica · 2026Review
- Single-cell polygenic risk scores dissect cellular and molecular heterogeneity of complex human diseases.Nature biotechnology · 2026Article
- The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.Neurology. Genetics · 2026Article
- RNA-seq variants reveal distinct patterns in the aging epitranscriptome: an in-depth analysis of age-matched Alzheimer's Disease patients and a cognitively normal cohort.bioRxiv : the preprint server for biology · 2026Article
- Physiological and pathological roles of ANXA11: a multifunctional regulator in neurodegeneration and other disorders.Cell communication and signaling : CCS · 2026Review
- ANXA11 Variant-Associated Adult-Onset Myopathy: A Novel Phenotype.Annals of Indian Academy of Neurology · 2026Article
- Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease.Acta neuropathologica · 2025Article
- Article
- Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort.Journal of neurology · 2025Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- ANXA11 Mutations in the FTD Spectrum: A Novel Finding in a Patient With Semantic Variant Primary Progressive Aphasia.European journal of neurology · 2025Article
- TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.Cell reports · 2025Article
- An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
- Update ofAn2023
Authors and funding
21 authors.
Funding
Abstract
introductionVariants 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.
methodsWe 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.
resultsANXA11 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. DISCUSSION: 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. HIGHLIGHTS: 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.
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