| ANXA11 — Annexin A11 | |
|---|---|
| Symbol | ANXA11 |
| Full Name | Annexin A11 |
| Chromosome | 10q22.3 |
| NCBI Gene | 311 |
| Ensembl | ENSG00000122359 |
| OMIM | 602572 |
| UniProt | P50995 |
| Diseases | ALS, FTD, ALS-FTD |
| Expression | Motor neurons, Cortex, Hippocampus, Spinal cord |
| Key Mutations | |
| p.D40G (LCD; ALS-FTD) p.G38R (founder variant) p.R235Q (calcium domain) p.R346C (annexin repeat) |
|
Anxa11 (Annexin A11) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
ANXA11 (Annexin A11) is a gene located on chromosome 10q22.3 that encodes annexin A11, a calcium-dependent phospholipid-binding protein belonging to the annexin superfamily.
ANXA11 was identified as a novel [amyotrophic lateral sclerosis (ALS)[/diseases/als gene in 2017, and subsequent studies have established it as an important genetic contributor to the ALS-[Frontotemporal Dementia (FTD)[/diseases/ftd spectrum
[1][3].
Mutations in ANXA11 account for approximately 1–2% of familial ALS cases and a smaller fraction of sporadic ALS [1].
The annexin A11 protein is unique among annexins due to its long N-terminal low-complexity domain (LCD), which mediates interactions with RNA granules and [stress granules[/mechanisms/stress-granules.
ALS-linked mutations disrupt calcium homeostasis, stress granule dynamics, and nuclear envelope integrity, connecting ANXA11 to the converging pathogenic pathways of [RNA metabolism[/mechanisms/rna-metabolism dysfunction and [protein aggregation[/mechanisms/protein-aggregation
in Motor [Neuron[/entities/neurons Disease [2][4].
The gene is catalogued as NCBI Gene ID [311] and OMIM [602572].
Annexin A11 is a 505-amino-acid protein with two distinct functional domains:
N-terminal low-complexity domain (LCD, residues 1–188): An intrinsically disordered region enriched in glycine and proline residues.
This domain mediates [liquid-liquid phase separation[/mechanisms/liquid-liquid-phase-separation (LLPS) and interactions with RNA granules, [stress granules[/mechanisms/stress-granules, and P-bodies.
It also contains a calcyclin-binding domain [1][2].
C-terminal annexin core (residues 189–505): Contains four conserved annexin repeats that bind calcium ions and phospholipids, enabling membrane association. The annexin core mediates calcium-dependent binding to cellular membranes, lysosomes, and the nuclear envelope [4].
Expression data is available from the Allen Human Brain Atlas.
ANXA11 mutations are linked to the following neurodegenerative conditions:
Mutations cluster primarily in two regions: the N-terminal LCD and the calcium-binding annexin repeats [1][3]:
Low-Complexity Domain Mutations:
Annexin Core Mutations:
Clinical Correlations:
Patients with variants in the low-complexity domain presented unique clinical features, including late-onset disease (mean ~60 years), a high prevalence of ALS-FTD overlap, faster initial progression, and a tendency for
bulbar-onset disease [3].
In a Chinese ALS cohort of 1,587 patients, ANXA11 variants were found in 29 patients (1.8%), with 20 distinct non-synonymous variants
identified [1][2].
ALS-linked ANXA11 mutations impair the normal dynamics of stress granules — cytoplasmic RNA-protein condensates that form in response to cellular stress.
Wild-type ANXA11 promotes stress granule disassembly during stress recovery; mutant forms fail to properly dissolve stress granules, leading to their persistence and potential conversion into pathological aggregates
[2].
This connects ANXA11 to the broader paradigm of [RNA metabolism[/mechanisms/rna-metabolism dysfunction in ALS, alongside [TDP-43[/proteins/tdp-43, [FUS[/proteins/fus-protein, and other RNA-binding proteins.
Annexin repeat mutations directly impair calcium-dependent membrane binding. LCD mutations also cause secondary calcium dysregulation by altering the protein's interaction with membranes and organelles. Disturbed calcium homeostasis activates downstream cascades including [excitotoxicity[/entities/excitotoxicity, mitochondrial stress, and apoptotic signaling [2].
Studies in Drosophila models and human tissues demonstrate that ANXA11 mutations cause nuclear envelope defects, including abnormal nuclear morphology, disrupted nuclear lamina organization, and impaired nucleocytoplasmic transport [4]. This mechanism parallels nuclear pore complex dysfunction observed with [C9orf72[/genes/c9orf72 repeat expansions and connects to [nucleocytoplasmic transport defects[/mechanisms/nucleocytoplasmic-transport-defects as a convergent ALS mechanism.
ANXA11's role as a molecular tether between RNA granules and lysosomes is critical for mRNA delivery along the long axons of [motor neurons[/cell-types/motor-neurons.
ALS mutations disrupt this tethering function, potentially starving distal axonal compartments of essential mRNAs for local protein
synthesis — contributing to the dying-back axonopathy characteristic of ALS [2][4].
The study of Anxa11 (Annexin A11) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.