Robaszkiewicz, K;
Siatkowska, M;
Wadman, RI;
Kamsteeg, EJ;
Chen, Z;
Merve, A;
Parton, M;
... Moraczewska, J; + view all
(2023)
A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.
International Journal of Molecular Sciences
, 24
(22)
, Article 16147. 10.3390/ijms242216147.
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Abstract
A novel variant of unknown significance c.8A > G (p.Glu3Gly) in TPM3 was detected in two unrelated families. TPM3 encodes the transcript variant Tpm3.12 (NM_152263.4), the tropomyosin isoform specifically expressed in slow skeletal muscle fibers. The patients presented with slowly progressive muscle weakness associated with Achilles tendon contractures of early childhood onset. Histopathology revealed features consistent with a nemaline rod myopathy. Biochemical in vitro assays performed with reconstituted thin filaments revealed defects in the assembly of the thin filament and regulation of actin–myosin interactions. The substitution p.Glu3Gly increased polymerization of Tpm3.12, but did not significantly change its affinity to actin alone. Affinity of Tpm3.12 to actin in the presence of troponin ± Ca2+ was decreased by the mutation, which was due to reduced interactions with troponin. Altered molecular interactions affected Ca2+-dependent regulation of the thin filament interactions with myosin, resulting in increased Ca2+ sensitivity and decreased relaxation of the actin-activated myosin ATPase activity. The hypercontractile molecular phenotype probably explains the distal joint contractions observed in the patients, but additional research is needed to explain the relatively mild severity of the contractures. The slowly progressive muscle weakness is most likely caused by the lack of relaxation and prolonged contractions which cause muscle wasting. This work provides evidence for the pathogenicity of the TPM3 c.8A > G variant, which allows for its classification as (likely) pathogenic.
| Type: | Article |
|---|---|
| Title: | A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/ijms242216147 |
| Publisher version: | http://dx.doi.org/10.3390/ijms242216147 |
| Language: | English |
| Additional information: | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | nemaline myopathy, pathogenic variant, thin filament, tropomyosin, Humans, Child, Preschool, Actins, Tropomyosin, Muscle Weakness, Myopathies, Nemaline, Mutation, Myosins, Contracture, Phenotype, Troponin, Muscle, Skeletal |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10183668 |
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