ArticleHuman molecular genetics2013
Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed.
- Integrative Approaches to Myopathies and Muscular Dystrophies: Molecular Mechanisms, Diagnostics, and Future Therapies.International journal of molecular sciences · 2025Review
- The Twisting and Untwisting of Actin and Tropomyosin Filaments Are Involved in the Molecular Mechanisms of Muscle Contraction, and Their Disruption Can Result in Muscle Disorders.International journal of molecular sciences · 2025Review
- Article
- Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.ESC heart failure · 2024Article
- Myotube Guidance: Shaping up the Musculoskeletal System.Journal of developmental biology · 2024Review
- Glutamate 139 of tropomyosin is critical for cardiac thin filament blocked-state stabilization.Journal of molecular and cellular cardiology · 2024Article
- Actin Polymerization Defects Induce Mitochondrial Dysfunction in Cellular Models of Nemaline Myopathies.Antioxidants (Basel, Switzerland) · 2023Article
- RBFOX2 regulated EYA3 isoforms partner with SIX4 or ZBTB1 to control transcription during myogenesis.iScience · 2023Article
- A Novel Variant inInternational journal of molecular sciences · 2023Article
- Tropomyosin 3 (TPM3) function in skeletal muscle and in myopathy.Skeletal muscle · 2023Review
- A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy - a case report.BMC neurology · 2023Article
- Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents.International journal of molecular sciences · 2023Article
- Transcript-Based Diagnosis and Expanded Phenotype of an Intronic Mutation in TPM3 Myopathy.Molecular diagnosis & therapy · 2022Article
- A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis.JCI insight · 2022Article
- Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of This Effect by BDM and W7.International journal of molecular sciences · 2021Article
- Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by GlnInternational journal of molecular sciences · 2020Article
- Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy.Acta neuropathologica communications · 2020Article
- The actin 'A-triad's' role in contractile regulation in health and disease.The Journal of physiology · 2020Review
- Molecular Mechanisms of Muscle Weakness Associated with E173A Mutation in Tpm3.12. Troponin CaInternational journal of molecular sciences · 2020Article
- Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin.International journal of molecular sciences · 2020Article
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Authors and funding
10 authors.
Funding
Abstract
The congenital myopathies include a wide spectrum of clinically, histologically and genetically variable neuromuscular disorders many of which are caused by mutations in genes for sarcomeric proteins. Some congenital myopathy patients have a hypercontractile phenotype. Recent functional studies demonstrated that ACTA1 K326N and TPM2 ΔK7 mutations were associated with hypercontractility that could be explained by increased myofibrillar Ca(2+) sensitivity. A recent structure of the complex of actin and tropomyosin in the relaxed state showed that both these mutations are located in the actin-tropomyosin interface. Tropomyosin is an elongated molecule with a 7-fold repeated motif of around 40 amino acids corresponding to the 7 actin monomers it interacts with. Actin binds to tropomyosin electrostatically at two points, through Asp25 and through a cluster of amino acids that includes Lys326, mutated in the gain-of-function mutation. Asp25 interacts with tropomyosin K6, next to K7 that was mutated in the other gain-of-function mutation. We identified four tropomyosin motifs interacting with Asp25 (K6-K7, K48-K49, R90-R91 and R167-K168) and three E-E/D-K/R motifs interacting with Lys326 (E139, E181 and E218), and we predicted that the known skeletal myopathy mutations ΔK7, ΔK49, R91G, ΔE139, K168E and E181K would cause a gain of function. Tests by an in vitro motility assay confirmed that these mutations increased Ca(2+) sensitivity, while mutations not in these motifs (R167H, R244G) decreased Ca(2+) sensitivity. The work reported here explains the molecular mechanism for 6 out of 49 known disease-causing mutations in the TPM2 and TPM3 genes, derived from structural data of the actin-tropomyosin interface.
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