TIA1 – Welander Distal Myopathy

TIA1 encodes an RNA-binding protein that regulates stress granule (SG) dynamics and alternative pre-mRNA splicing. Welander distal myopathy (WDM) is a late-onset autosomal dominant distal myopathy characterized by weakness of the hands and feet (MONDO:0011466). The founder TIA1 c.1150G>A (p.Glu384Lys) variant underlies WDM and exhibits a striking genotype–phenotype correlation across multiple Nordic families.

Genetic studies have demonstrated autosomal dominant inheritance of WDM with the TIA1 variant segregating in multiple unrelated Swedish and Finnish families (n = 43 probands) (PMID:23348830). Affected individuals exhibit distal long extensor muscle weakness and rimmed vacuoles on biopsy. Segregation of c.1150G>A (p.Glu384Lys) was confirmed in a distinct non-Nordic family (one affected sibling pair) (PMID:28221306). No other coding variants in TIA1 or alternative loci were identified in linked haplotypes.

Variant spectrum remains restricted to the founder c.1150G>A (p.Glu384Lys) variant in TIA1, with no additional pathogenic alleles reported in monogenic WDM. Digenic interactions involving TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu have been proposed but lack broad replication in WDM cohorts.

Functional assays demonstrate that p.Glu384Lys perturbs SG dynamics and RNA splicing. Muscle biopsies from patients show TIA1 and stress granule protein accumulation adjacent to vacuolated fibers, and SMN2 exon 7 splicing is altered in patient-derived myoblasts (PMID:23348830). In HeLa cell models, mutant TIA1 exhibits increased SG formation and reduced fluorescence recovery after photobleaching (PMID:23401021), while ectopic expression of TIA1-E384K in kidney cells recapitulates stress granule persistence, mitochondrial dysfunction, and autophagy (PMID:30348840). Live-cell imaging further shows delayed SG disassembly for E384K compared to wild type (PMID:35269506).

These data support a dominant toxic gain-of-function mechanism for TIA1 in WDM, driven by altered SG assembly/disassembly and downstream perturbation of RNA metabolism. The consistent genotype–phenotype linkage and concordant in vivo and in vitro functional results provide a robust foundation for clinical genetic testing and patient stratification.

Key Take-Home: The TIA1 c.1150G>A (p.Glu384Lys) variant has a definitive association with Welander distal myopathy and is recommended for inclusion in diagnostic gene panels.

References

• Human mutation • 2013 • Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing PMID:23348830
• Journal of clinical neuromuscular disease • 2017 • Whole Exome Sequencing Identifies Atypical Welander Distal Myopathy in Patient PMID:28221306
• Annals of neurology • 2013 • Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1 PMID:23401021
• Molecular and cellular biology • 2019 • A Heterologous Cell Model for Studying the Role of T-Cell Intracellular Antigen 1 in Welander Distal Myopathy PMID:30348840
• Cells • 2022 • Dynamics of T-Cell Intracellular Antigen 1-Dependent Stress Granules in Proteostasis and Welander Distal Myopathy under Oxidative Stress PMID:35269506

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