ArticleThe Journal of clinical investigation2018
TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 108 citations in OpenAlex.
- Review
- Review
- Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy.Annals of clinical and translational neurology · 2026Article
- Expression Patterns of T-Cell Intracellular Antigen 1 in Neurodegenerative Disorders and Stroke.International journal of molecular sciences · 2026Review
- Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.The EMBO journal · 2025Article
- Structural basis for T-cell intracellular antigen-1 amyloid fibril formation revealed by cryo-electron microscopy.PNAS nexus · 2025Article
- Translating Muscle RNAseq Into the Clinic for the Diagnosis of Muscle Diseases.Annals of clinical and translational neurology · 2025Article
- Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.Frontiers in molecular neuroscience · 2025Review
- Seeding-competent TDP-43 persists in human patient and mouse muscle.Science translational medicine · 2024Article
- Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.Disease models & mechanisms · 2024Review
- Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.International journal of molecular sciences · 2024Review
- Seeding competent TDP-43 persists in human patient and mouse muscle.bioRxiv : the preprint server for biology · 2024Article
- Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.Nature genetics · 2024Article
- Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways.Human molecular genetics · 2023Article
- The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases-The Symptomatic Heterozygote Issue.Genes · 2023Review
- Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathological-molecular spectrum.Annals of clinical and translational neurology · 2023Article
- MYTHO is a novel regulator of skeletal muscle autophagy and integrity.Nature communications · 2023Article
- Integration of multi-omics technologies for molecular diagnosis in ataxia patients.Frontiers in genetics · 2023Article
- Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report.Frontiers in neurology · 2023Article
- Adult-onset dominant muscular dystrophy in Greek families caused by Annexin A11.Annals of clinical and translational neurology · 2022Article
Corrections and comments
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Authors and funding
28 authors at 13 institutions in 6 countries.
Funding
Abstract
Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.
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Registered trials
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