ANXA11 – Amyotrophic lateral sclerosis

ANXA11 has emerged as a heterozygous dominant gene implicated in adult-onset amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis). Initial exome sequencing of 751 familial ALS cases identified six distinct ANXA11 missense mutations in 13 affected individuals, including the recurrent c.119A>G (p.Asp40Gly) variant that segregated in two kindreds (PMID:28469040). Subsequent screening across diverse populations uncovered 68 probands carrying 29 separate ANXA11 variants, supporting a consistent association with ALS phenotypes (PMID:36873447).

Inheritance is autosomal dominant with segregation confirmed in multiple families and de novo occurrences in sporadic cases. Reported variants span the N-terminal low-complexity domain and C-terminal annexin repeats, including missense changes, splice-site alterations, and frameshifts. The hotspot variant c.119A>G (p.Asp40Gly) recurs in both familial and sporadic ALS and defines a founder haplotype in European populations (PMID:28469040).

Functional studies demonstrate that N-terminal variants (p.Gly38Arg, p.Asp40Gly) enhance ANXA11 aggregation propensity and impair stress granule disassembly, while C-terminal mutations (p.His390Pro, p.Arg456His) alter calcium responses, collectively inducing toxic gain-of-function in neuronal models and patient tissues (PMID:33087501). Patient-derived fibroblasts and iPSC-derived neurons exhibit dysregulated Ca2+ homeostasis, persistent ANXA11 inclusions, and TDP-43 co-aggregation mirroring neuropathology.

No robust conflicting evidence has yet refuted the ANXA11–ALS link, although rare variants of uncertain significance (e.g., p.Gln362Leu) remain to be functionally characterized. Overall, genetic and experimental data converge on a mechanism of altered protein aggregation and intracellular trafficking leading to motor neuron degeneration.

Key take-home: Heterozygous ANXA11 missense mutations, notably c.119A>G (p.Asp40Gly), confer autosomal dominant ALS risk via toxic gain-of-function, providing actionable targets for genetic diagnosis and personalized therapy.

References

• Science translational medicine • 2017 • Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. PMID:28469040
• Science translational medicine • 2020 • ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics. PMID:33087501
• Frontiers in neurology • 2023 • An atypical ALS with PSP-like symptoms caused by ANXA11 p.D40G mutation: A case report and literature review. PMID:36873447
• ANXA11
• Amyotrophic lateral sclerosis

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