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New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy

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Abstract

Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomeric proteins. Its variable phenotype suggests the existence of modifier genes. Myocyte enhancer factor (MEF) 2C could be important in this process given its role as transcriptional regulator of several cardiac genes. Any variant affecting MEF2C expression and/or function may impact on hypertrophic cardiomyopathy clinical manifestations. In this candidate gene approach, we screened 209 Caucasian hypertrophic cardiomyopathy patients and 313 healthy controls for genetic variants in MEF2C gene by single-strand conformation polymorphism analysis and direct sequencing. Functional analyses were performed with transient transfections of luciferase reporter constructions. Three new variants in non-coding exon 1 were found both in patients and controls with similar frequencies. One-way ANOVA analyses showed a greater left ventricular outflow tract obstruction (p = 0.011) in patients with 10C+10C genotype of the c.-450C(8_10) variant. Moreover, one patient was heterozygous for two rare variants simultaneously. This patient presented thicker left ventricular wall than her relatives carrying the same sarcomeric mutation. In vitro assays additionally showed a slightly increased transcriptional activity for both rare MEF2C alleles. In conclusion, our data suggest that 15 bp-deletion and C-insertion in the 5′UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C and therefore, the expression of their target cardiac proteins that are implicated in the hypertrophic process.

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Acknowledgments

We thank the patients and their families that consent to participate in this study. This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias-Fondos FEDER European Union (FIS 07/0659, 10/00173), and Red de Investigación Renal-REDinREN (RD06/0016) from Instituto de Salud Carlos III. CAM and IR were financially supported by the Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (FICYT).

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Authors and Affiliations

  1. Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Oviedo, Spain

    Cristina Alonso-Montes, Manuel Naves-Diaz, Jose Luis Fernandez-Martin, Jorge B. Cannata-Andia & Isabel Rodriguez

  2. Red Temática de Investigación Cooperativa REDinREN, Oviedo, Spain

    Manuel Naves-Diaz, Jose Luis Fernandez-Martin, Eliecer Coto, Jorge B. Cannata-Andia & Isabel Rodriguez

  3. Área del Corazón-Fundación Asturcor, Hospital Universitario Central de Asturias, Oviedo, Spain

    Julian Rodriguez-Reguero & Cesar Moris

  4. Unidad de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain

    Eliecer Coto

  5. Department of Medicine, University of Oviedo, Oviedo, Spain

    Eliecer Coto & Jorge B. Cannata-Andia

  6. Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias, Edif. Polivalente A, 2a pl., C/Julián Clavería, s/n, 33006, Oviedo, Spain

    Isabel Rodriguez

  7. Instituto Reina Sofía de Investigación Nefrológica, Oviedo, Spain

    Cristina Alonso-Montes, Manuel Naves-Diaz, Jose Luis Fernandez-Martin, Eliecer Coto, Jorge B. Cannata-Andia & Isabel Rodriguez

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  1. Cristina Alonso-Montes
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  2. Manuel Naves-Diaz
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Correspondence to Isabel Rodriguez.

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Alonso-Montes, C., Naves-Diaz, M., Fernandez-Martin, J.L. et al. New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy. Mol Biol Rep 39, 8777–8785 (2012). https://doi.org/10.1007/s11033-012-1740-7

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