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A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.

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Title: A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.
Authors: Robaszkiewicz, Katarzyna1 (AUTHOR) robkat@ukw.edu.pl, Siatkowska, Małgorzata1 (AUTHOR) gosia.sl@ukw.edu.pl, Wadman, Renske I.2 (AUTHOR) r.i.wadman@umcutrecht.nl, Kamsteeg, Erik-Jan3 (AUTHOR) erik-jan.kamsteeg@radboudumc.nl, Chen, Zhiyong4,5 (AUTHOR) zhiyong.chen@nhs.net, Merve, Ashirwad6 (AUTHOR) amerve@nhs.not, Parton, Matthew4 (AUTHOR) matt.parton@nhs.net, Bugiardini, Enrico4 (AUTHOR) e.bugardini@ucl.ac.uk, de Bie, Charlotte7 (AUTHOR) c.i.debie-2@umcutrecht.nl, Moraczewska, Joanna1 (AUTHOR) joanna.moraczewska@ukw.edu.pl
Source: International Journal of Molecular Sciences. Nov2023, Vol. 24 Issue 22, p16147. 15p.
Subject Terms: *NEMALINE myopathy, *MUSCLE weakness, *MYOSIN, *ACHILLES tendon, *PHENOTYPES, *SKELETAL muscle, *MOLECULAR interactions
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. [ABSTRACT FROM AUTHOR]
Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.
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  Data: <searchLink fieldCode="AR" term="%22Robaszkiewicz%2C+Katarzyna%22">Robaszkiewicz, Katarzyna</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> robkat@ukw.edu.pl</i><br /><searchLink fieldCode="AR" term="%22Siatkowska%2C+Małgorzata%22">Siatkowska, Małgorzata</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> gosia.sl@ukw.edu.pl</i><br /><searchLink fieldCode="AR" term="%22Wadman%2C+Renske+I%2E%22">Wadman, Renske I.</searchLink><relatesTo>2</relatesTo> (AUTHOR)<i> r.i.wadman@umcutrecht.nl</i><br /><searchLink fieldCode="AR" term="%22Kamsteeg%2C+Erik-Jan%22">Kamsteeg, Erik-Jan</searchLink><relatesTo>3</relatesTo> (AUTHOR)<i> erik-jan.kamsteeg@radboudumc.nl</i><br /><searchLink fieldCode="AR" term="%22Chen%2C+Zhiyong%22">Chen, Zhiyong</searchLink><relatesTo>4,5</relatesTo> (AUTHOR)<i> zhiyong.chen@nhs.net</i><br /><searchLink fieldCode="AR" term="%22Merve%2C+Ashirwad%22">Merve, Ashirwad</searchLink><relatesTo>6</relatesTo> (AUTHOR)<i> amerve@nhs.not</i><br /><searchLink fieldCode="AR" term="%22Parton%2C+Matthew%22">Parton, Matthew</searchLink><relatesTo>4</relatesTo> (AUTHOR)<i> matt.parton@nhs.net</i><br /><searchLink fieldCode="AR" term="%22Bugiardini%2C+Enrico%22">Bugiardini, Enrico</searchLink><relatesTo>4</relatesTo> (AUTHOR)<i> e.bugardini@ucl.ac.uk</i><br /><searchLink fieldCode="AR" term="%22de+Bie%2C+Charlotte%22">de Bie, Charlotte</searchLink><relatesTo>7</relatesTo> (AUTHOR)<i> c.i.debie-2@umcutrecht.nl</i><br /><searchLink fieldCode="AR" term="%22Moraczewska%2C+Joanna%22">Moraczewska, Joanna</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> joanna.moraczewska@ukw.edu.pl</i>
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  Data: <searchLink fieldCode="JN" term="%22International+Journal+of+Molecular+Sciences%22">International Journal of Molecular Sciences</searchLink>. Nov2023, Vol. 24 Issue 22, p16147. 15p.
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  Data: *<searchLink fieldCode="DE" term="%22NEMALINE+myopathy%22">NEMALINE myopathy</searchLink><br />*<searchLink fieldCode="DE" term="%22MUSCLE+weakness%22">MUSCLE weakness</searchLink><br />*<searchLink fieldCode="DE" term="%22MYOSIN%22">MYOSIN</searchLink><br />*<searchLink fieldCode="DE" term="%22ACHILLES+tendon%22">ACHILLES tendon</searchLink><br />*<searchLink fieldCode="DE" term="%22PHENOTYPES%22">PHENOTYPES</searchLink><br />*<searchLink fieldCode="DE" term="%22SKELETAL+muscle%22">SKELETAL muscle</searchLink><br />*<searchLink fieldCode="DE" term="%22MOLECULAR+interactions%22">MOLECULAR interactions</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.3390/ijms242216147
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      – Code: eng
        Text: English
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        PageCount: 15
        StartPage: 16147
    Subjects:
      – SubjectFull: NEMALINE myopathy
        Type: general
      – SubjectFull: MUSCLE weakness
        Type: general
      – SubjectFull: MYOSIN
        Type: general
      – SubjectFull: ACHILLES tendon
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      – SubjectFull: PHENOTYPES
        Type: general
      – SubjectFull: SKELETAL muscle
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      – SubjectFull: MOLECULAR interactions
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      – TitleFull: A Novel Variant in TPM3 Causing Muscle Weakness and Concomitant Hypercontractile Phenotype.
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              Text: Nov2023
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