Common pathophysiology for ANXA11 disorders caused by aspartate 40 variants

Area of Science:

• Genetics and Molecular Biology
• Neuromuscular Disorders
• Protein Biochemistry

Background:

• Mutations in the ANXA11 gene are linked to amyotrophic lateral sclerosis (ALS), multisystem proteinopathy, and adult-onset muscular dystrophy.
• These diseases stem from substitutions at Aspartate 40 (Asp40) in the intrinsically disordered domain (IDD) of ANXA11, but the mechanism of myopathy remains unclear.

Purpose of the Study:

• To investigate the pathogenic mechanism of a novel ANXA11 variant (p.Asp40Ile) identified in a patient with severe childhood-onset oculopharyngeal muscular dystrophy.
• To explore the common pathophysiology underlying ANXA11 Asp40-related neuromuscular disorders.

Main Methods:

• Whole-exome sequencing (WES-trio) for genetic analysis.
• In vitro studies using recombinant ANXA11 proteins to assess variant pathogenicity.
• Analysis of patient muscle biopsy and fibroblasts, including super-resolution imaging.

Main Results:

• The novel ANXA11 p.Asp40Ile variant significantly enhances protein aggregation propensity and causes abnormal phase separation in vitro, more so than the ALS-associated p.Asp40Gly variant.
• Patient fibroblasts exhibited impaired stress granule dynamics and clearance.
• Muscle histopathology revealed ANXA11 aggregates within muscle fibers, appearing as pearl strips or complex structures, and subsarcolemmal chains.

Conclusions:

• A common pathophysiology exists for ANXA11 Asp40 allelic variant-associated disorders, driven by differential impacts on protein aggregation stability.
• Clinical phenotypes arise from a temporal and tissue-specific continuum of muscle or motor neuron dysfunction.
• The findings highlight ANXA11's role in neuromuscular disease and provide insights into the variable clinical presentations.