Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation
<p style="text-align:justify;">We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to s...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2016
|
| _version_ | 1797107093103181824 |
|---|---|
| author | Messer, A Bayliss, C El-Mezgueldi, M Redwood, C Ward, D Leung, M Papadaki, M Dos Remedios, C Marston, S |
| author_facet | Messer, A Bayliss, C El-Mezgueldi, M Redwood, C Ward, D Leung, M Papadaki, M Dos Remedios, C Marston, S |
| author_sort | Messer, A |
| collection | OXFORD |
| description | <p style="text-align:justify;">We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to study Ca2+-regulation of unloaded movement and its modulation by troponin I phosphorylation. Troponin from a patient with the K280N TnT mutation showed no difference in Ca2+-sensitivity when compared with donor heart troponin and the Ca2+-sensitivity was also independent of the troponin I phosphorylation level (uncoupled). The recombinant K280N TnT mutation increased Ca2+-sensitivity 1.7-fold and was also uncoupled. The R92Q TnT mutation in troponin from transgenic mouse increased Ca2+-sensitivity and was also completely uncoupled. Five TnT mutations (Δ14, Δ28 + 7, ΔE160, S179F and K273E) studied in recombinant troponin increased Ca2+-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutations in TnT, Ca2+-sensitisation together with uncoupling in vitro is the usual response and both factors may contribute to the HCM phenotype. We also found that Epigallocatechin-3-gallate (EGCG) can restore coupling to all uncoupled HCM-causing TnT mutations. In fact the combination of Ca2+-desensitisation and re-coupling due to EGCG completely reverses both the abnormalities found in troponin with a TnT HCM mutation suggesting it may have therapeutic potential.</p> |
| first_indexed | 2024-03-07T07:11:33Z |
| format | Journal article |
| id | oxford-uuid:eceebfc9-feaf-47ad-98b1-2f5a05456e4b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:11:33Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:eceebfc9-feaf-47ad-98b1-2f5a05456e4b2022-06-16T13:17:58ZMutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:eceebfc9-feaf-47ad-98b1-2f5a05456e4bEnglishSymplectic Elements at OxfordElsevier2016Messer, ABayliss, CEl-Mezgueldi, MRedwood, CWard, DLeung, MPapadaki, MDos Remedios, CMarston, S <p style="text-align:justify;">We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to study Ca2+-regulation of unloaded movement and its modulation by troponin I phosphorylation. Troponin from a patient with the K280N TnT mutation showed no difference in Ca2+-sensitivity when compared with donor heart troponin and the Ca2+-sensitivity was also independent of the troponin I phosphorylation level (uncoupled). The recombinant K280N TnT mutation increased Ca2+-sensitivity 1.7-fold and was also uncoupled. The R92Q TnT mutation in troponin from transgenic mouse increased Ca2+-sensitivity and was also completely uncoupled. Five TnT mutations (Δ14, Δ28 + 7, ΔE160, S179F and K273E) studied in recombinant troponin increased Ca2+-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutations in TnT, Ca2+-sensitisation together with uncoupling in vitro is the usual response and both factors may contribute to the HCM phenotype. We also found that Epigallocatechin-3-gallate (EGCG) can restore coupling to all uncoupled HCM-causing TnT mutations. In fact the combination of Ca2+-desensitisation and re-coupling due to EGCG completely reverses both the abnormalities found in troponin with a TnT HCM mutation suggesting it may have therapeutic potential.</p> |
| spellingShingle | Messer, A Bayliss, C El-Mezgueldi, M Redwood, C Ward, D Leung, M Papadaki, M Dos Remedios, C Marston, S Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title | Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title_full | Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title_fullStr | Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title_full_unstemmed | Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title_short | Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca2+-sensitivity and suppress the modulation of Ca2+-sensitivity by troponin I phosphorylation |
| title_sort | mutations in troponin t associated with hypertrophic cardiomyopathy increase ca2 sensitivity and suppress the modulation of ca2 sensitivity by troponin i phosphorylation |
| work_keys_str_mv | AT messera mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT baylissc mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT elmezgueldim mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT redwoodc mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT wardd mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT leungm mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT papadakim mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT dosremediosc mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation AT marstons mutationsintroponintassociatedwithhypertrophiccardiomyopathyincreaseca2sensitivityandsuppressthemodulationofca2sensitivitybytroponiniphosphorylation |