New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy.
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.
Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
Cristina
C
Alonso-Montes
Manuel
M
Naves-Diaz
Jose Luis
JL
Fernandez-Martin
Julian
J
Rodriguez-Reguero
Cesar
C
Moris
Eliecer
E
Coto
Jorge B
JB
Cannata-Andia
Isabel
I
Rodriguez
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D060045:Genes, Modifier; D005838:Genotype; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics*; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic; D014463:Ultrasonography
D020121:5' Untranslated Regions; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors