Effects of myopathy-causing mutations R91P and R245G in the TPM3 gene on structural and functional properties of slow skeletal muscle tropomyosin

Tropomyosin (Tpm) is an actin-binding protein that plays a crucial role in the regulation of muscle contraction. Numerous point mutations in the TPM3 gene encoding Tpm of slow skeletal muscles (Tpm 3.12 or gamma-Tpm) are associated with the genesis of various congenital myopathies. Two of these mutations, R91P and R245G, are associated with congenital fiber-type disproportion (CFTD) characterized by hypotonia and generalized muscle weakness. We applied various methods to investigate how these mutations affect the structural and functional properties of gamma gamma-Tpm homodimers. The results show that both these mutations lead to strong structural changes in the gamma gamma-Tpm molecule and significantly impaired its functional properties. These changes in the Tpm properties caused by R91P and R245G mutations give insight into the molecular mechanism of the CFTD development and the weakness of slow skeletal muscles observed in this inherited disease. (C) 2020 Elsevier Inc. All rights reserved.

Automated summary

Mutations in the TPM3 gene cause structural changes and impaired functional properties in the gamma gamma-Tpm molecule, shedding light on the molecular mechanism of CFTD development and slow skeletal muscle weakness in this inherited disease.