Home Medicine Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy
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Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy

  • Qi Qiao , Cui-Mei Zhao , Chen-Xi Yang , Jia-Ning Gu , Yu-Han Guo , Min Zhang , Ruo-Gu Li , Xing-Biao Qiu , Ying-Jia Xu and Yi-Qing Yang EMAIL logo
Published/Copyright: December 3, 2020
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 59 Issue 5

Abstract

Objectives

Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.

Methods

Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system.

Results

A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM.

Conclusions

The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.

Keywords: cardiomyopathy; genetics; luciferase assay; MEF2A; transcriptional factor
Corresponding author: Dr. Yi-Qing Yang, Department of Cardiology, Shanghai Fifth People′s Hospital, Fudan University, Shanghai, P.R. China; Cardiovascular Research Laboratory, Shanghai Fifth People′s Hospital, Fudan University, Shanghai, P.R. China; and Center Laboratory, Shanghai Fifth People′s Hospital, Fudan University, Shanghai, P.R. China, Phone: +86 21 24289657, Fax: +86 21 24289657, E-mail:
Qi Qiao and Cui-Mei Zhao contributed equally to this work.

Funding source: Basic Research Project of Shanghai, China

Award Identifier / Grant number: 20JC1418800

Funding source: Science and Technology Support Project of Medical Guidance, Shanghai, China

Award Identifier / Grant number: 19411971900

Funding source: Clinical Research Project of Tongji Hospital, Tongji University, Shanghai, China

Award Identifier / Grant number: ITJ(QN)1803

Funding source: Experimental Animal Project of Shanghai, China

Award Identifier / Grant number: 201409004400

Funding source: Program of Outstanding Young Scientists of Tongji Hospital, Tongji University, Shanghai, China

Award Identifier / Grant number: HBRC1803

Funding source: Clinical Medicine Program of Shanghai, China

Award Identifier / Grant number: 19401970200

Acknowledgments

The authors would like to thank the research participants for participation in the research.

  1. Research funding: This work was supported by the grants from the Basic Research Project of Shanghai, China (20JC1418800), the Experimental Animal Project of Shanghai, China (201409004400), the Clinical Medicine Program of Shanghai, China (19401970200), the Science and Technology Support Project of Medical Guidance, Shanghai, China (19411971900), the Program of Outstanding Young Scientists of Tongji Hospital, Tongji University, Shanghai, China (HBRC1803), and the Clinical Research Project of Tongji Hospital, Tongji University, Shanghai, China (ITJ(QN) 1803).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the Medical Ethics Committee of Shanghai Fifth People′s Hospital, Fudan University, Shanghai, China.

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Received: 2020-08-29
Accepted: 2020-11-25
Published Online: 2020-12-03
Published in Print: 2021-04-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2020-1318
Keywords for this article
cardiomyopathy; genetics; luciferase assay; MEF2A; transcriptional factor

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Home pregnancy tests: quality first
  4. Review
  5. Non-invasive determination of uric acid in human saliva in the diagnosis of serious disorders
  6. Opinion Papers
  7. Basophil counting in hematology analyzers: time to discontinue?
  8. The role of laboratory hematology between technology and professionalism: the paradigm of basophil counting
  9. Recommendations for validation testing of home pregnancy tests (HPTs) in Europe
  10. General Clinical Chemistry and Laboratory Medicine
  11. The use of preanalytical quality indicators: a Turkish preliminary survey study
  12. The Italian External Quality Assessment (EQA) program on urinary sediment by microscopy examination: a 20 years journey
  13. Non-HDL-C/TG ratio indicates significant underestimation of calculated low-density lipoprotein cholesterol (LDL-C) better than TG level: a study on the reliability of mathematical formulas used for LDL-C estimation
  14. Evaluation of the protein gap for detection of abnormal serum gammaglobulin level: an imperfect predictor
  15. Impact of routine S100B protein assay on CT scan use in children with mild traumatic brain injury
  16. Using machine learning to develop an autoverification system in a clinical biochemistry laboratory
  17. Effect of collection matrix, platelet depletion, and storage conditions on plasma extracellular vesicles and extracellular vesicle-associated miRNAs measurements
  18. Pneumatic tube transportation of urine samples
  19. Evaluation of the first immunosuppressive drug assay available on a fully automated LC-MS/MS-based clinical analyzer suggests a new era in laboratory medicine
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  27. Evaluation of the ARKRAY HA-8190V instrument for HbA1c
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  32. The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study
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  34. Corrigendum to: Understanding and managing interferences in clinical laboratory assays: the role of laboratory professionals
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  38. Letter in reply to the letter to the editor of Harte JV and Mykytiv V with the title “A panhaemocytometric approach to COVID-19: a retrospective study on the importance of monocyte and neutrophil population data”
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  40. Long-term kinetics of anti-SARS-CoV-2 antibodies in a cohort of 197 hospitalized and non-hospitalized COVID-19 patients
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  44. Significant interference on specific point-of-care glucose measurements due to high dose of intravenous vitamin C therapy in critically ill patients
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  46. Stability of control materials for α-thalassemia immunochromatographic strip test
  47. Reformulated Architect® cyclosporine CMIA assay: improved imprecision, worse comparability between methods
  48. Urine-to-plasma contamination mimicking acute kidney injury: small drops with major consequences
  49. Automated Mindray CL-1200i chemiluminescent assays of renin and aldosterone for the diagnosis of primary aldosteronism
  50. Use of common reference intervals does not necessarily allow inter-method numerical result trending
  51. Reply to Dr Hawkins regarding comparability of results for monitoring
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