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Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila.
Dev Biol 2019; 449(2):90-98DB

Abstract

Missense mutations in the MYH3 gene encoding myosin heavy chain-embryonic (MyHC-embryonic) have been reported to cause two skeletal muscle contracture syndromes, Freeman Sheldon Syndrome (FSS) and Sheldon Hall Syndrome (SHS). Two residues in MyHC-embryonic that are most frequently mutated, leading to FSS, R672 and T178, are evolutionarily conserved across myosin heavy chains in vertebrates and Drosophila. We generated transgenic Drosophila expressing myosin heavy chain (Mhc) transgenes with the FSS mutations and characterized the effect of their expression on Drosophila muscle structure and function. Our results indicate that expressing these mutant Mhc transgenes lead to structural abnormalities in the muscle, which increase in severity with age and muscle use. We find that flies expressing the FSS mutant Mhc transgenes in the muscle exhibit shortening of the inter-Z disc distance of sarcomeres, reduction in the Z-disc width, aberrant deposition of Z-disc proteins, and muscle fiber splitting. The ATPase activity of the three FSS mutant MHC proteins are reduced compared to wild type MHC, with the most severe reduction observed in the T178I mutation. Structurally, the FSS mutations occur close to the ATP binding pocket, disrupting the ATPase activity of the protein. Functionally, expression of the FSS mutant Mhc transgenes in muscle lead to significantly reduced climbing capability in adult flies. Thus, our findings indicate that the FSS contracture syndrome mutations lead to muscle structural defects and functional deficits in Drosophila, possibly mediated by the reduced ATPase activity of the mutant MHC proteins.

Authors+Show Affiliations

Laboratory of Developmental Genetics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, 121001, India.Laboratory of Developmental Genetics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, 121001, India; Affiliated to Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.Laboratory of Developmental Genetics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, 121001, India.Functional Proteomics Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, 121001, India.Laboratory of Developmental Genetics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, 121001, India; Affiliated to Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India. Electronic address: sjmathew@rcb.res.in.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30826400

Citation

Das, Shreyasi, et al. "Myosin Heavy Chain Mutations That Cause Freeman-Sheldon Syndrome Lead to Muscle Structural and Functional Defects in Drosophila." Developmental Biology, vol. 449, no. 2, 2019, pp. 90-98.
Das S, Kumar P, Verma A, et al. Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. Dev Biol. 2019;449(2):90-98.
Das, S., Kumar, P., Verma, A., Maiti, T. K., & Mathew, S. J. (2019). Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. Developmental Biology, 449(2), pp. 90-98. doi:10.1016/j.ydbio.2019.02.017.
Das S, et al. Myosin Heavy Chain Mutations That Cause Freeman-Sheldon Syndrome Lead to Muscle Structural and Functional Defects in Drosophila. Dev Biol. 2019 May 15;449(2):90-98. PubMed PMID: 30826400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. AU - Das,Shreyasi, AU - Kumar,Pankaj, AU - Verma,Aakanksha, AU - Maiti,Tushar K, AU - Mathew,Sam J, Y1 - 2019/02/28/ PY - 2018/09/23/received PY - 2019/01/24/revised PY - 2019/02/27/accepted PY - 2019/3/4/pubmed PY - 2019/3/4/medline PY - 2019/3/4/entrez KW - Contracture KW - Drosophila KW - Freeman-Sheldon syndrome KW - Myosin heavy chain KW - Sarcomere KW - Skeletal muscle SP - 90 EP - 98 JF - Developmental biology JO - Dev. Biol. VL - 449 IS - 2 N2 - Missense mutations in the MYH3 gene encoding myosin heavy chain-embryonic (MyHC-embryonic) have been reported to cause two skeletal muscle contracture syndromes, Freeman Sheldon Syndrome (FSS) and Sheldon Hall Syndrome (SHS). Two residues in MyHC-embryonic that are most frequently mutated, leading to FSS, R672 and T178, are evolutionarily conserved across myosin heavy chains in vertebrates and Drosophila. We generated transgenic Drosophila expressing myosin heavy chain (Mhc) transgenes with the FSS mutations and characterized the effect of their expression on Drosophila muscle structure and function. Our results indicate that expressing these mutant Mhc transgenes lead to structural abnormalities in the muscle, which increase in severity with age and muscle use. We find that flies expressing the FSS mutant Mhc transgenes in the muscle exhibit shortening of the inter-Z disc distance of sarcomeres, reduction in the Z-disc width, aberrant deposition of Z-disc proteins, and muscle fiber splitting. The ATPase activity of the three FSS mutant MHC proteins are reduced compared to wild type MHC, with the most severe reduction observed in the T178I mutation. Structurally, the FSS mutations occur close to the ATP binding pocket, disrupting the ATPase activity of the protein. Functionally, expression of the FSS mutant Mhc transgenes in muscle lead to significantly reduced climbing capability in adult flies. Thus, our findings indicate that the FSS contracture syndrome mutations lead to muscle structural defects and functional deficits in Drosophila, possibly mediated by the reduced ATPase activity of the mutant MHC proteins. SN - 1095-564X UR - https://www.unboundmedicine.com/medline/citation/30826400/Myosin_heavy_chain_mutations_that_cause_Freeman-Sheldon_syndrome_lead_to_muscle_structural_and_functional_defects_in_Drosophila L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(18)30639-0 DB - PRIME DP - Unbound Medicine ER -