A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity
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A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity. / Friedrich, Felix W; Dilanian, Gilles; Khattar, Patricia; Juhr, Denise; Gueneau, Lucie; Charron, Philippe; Fressart, Véronique; Vilquin, Jean-Thomas; Isnard, Richard; Gouya, Laurent; Richard, Pascale; Hammoudi, Naima; Komajda, Michel; Bonne, Gisèle; Eschenhagen, Thomas; Dubourg, Olivier; Villard, Eric; Carrier, Lucie.
in: EUR J HEART FAIL, Jahrgang 15, Nr. 3, 01.03.2013, S. 267-76.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity
AU - Friedrich, Felix W
AU - Dilanian, Gilles
AU - Khattar, Patricia
AU - Juhr, Denise
AU - Gueneau, Lucie
AU - Charron, Philippe
AU - Fressart, Véronique
AU - Vilquin, Jean-Thomas
AU - Isnard, Richard
AU - Gouya, Laurent
AU - Richard, Pascale
AU - Hammoudi, Naima
AU - Komajda, Michel
AU - Bonne, Gisèle
AU - Eschenhagen, Thomas
AU - Dubourg, Olivier
AU - Villard, Eric
AU - Carrier, Lucie
PY - 2013/3/1
Y1 - 2013/3/1
N2 - AIMS: The transcription factor Islet-1 (ISL1) is a marker of cardiovascular progenitors and is essential for mammalian cardiogenesis. An ISL1 haplotype has recently been associated with congenital heart disease. In this study we evaluated whether ISL1 variants are associated with hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), or with Emery-Dreifuss muscular dystrophy (EDMD).METHODS AND RESULTS: The six exon and intron boundaries of ISL1 were screened for genetic variants in a cohort of 454 index cases. Eleven exonic variants were identified in HCM, DCM, ARVC, and/or EDMD. Out of the five novel variants, two are located in the 5'-untranslated region, two are silent (p.Arg171Arg and p.Asn189Asn), and one is a missense (p.Asn252Ser). The latter was identified in the homozygous state in one DCM patient, and in the heterozygous state in 11 relatives, who did not present with DCM but often with cardiovascular features. This variant was found in one HCM patient also carrying a MYH7 mutation and in 3/96 North-African Caucasian control individuals, but was absent in 138 European Caucasian control individuals. We investigated the effect of the ISL1 wild type and p.Asn252Ser mutant on myocyte enhancer factor 2C (Mef2c) promoter activity, an established ISL1 target. Mef2c promoter activity was ∼4-fold higher in the presence of wild-type and ∼6-fold higher in the presence of mutant ISL1 in both HEK and CHO cells.CONCLUSION: This study describes a new gain-of-function p.Asn252Ser variant in the human ISL1 gene, which could potentially lead to greater activation of downstream targets involved in cardiac development, dilation, and hypertrophy.
AB - AIMS: The transcription factor Islet-1 (ISL1) is a marker of cardiovascular progenitors and is essential for mammalian cardiogenesis. An ISL1 haplotype has recently been associated with congenital heart disease. In this study we evaluated whether ISL1 variants are associated with hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), or with Emery-Dreifuss muscular dystrophy (EDMD).METHODS AND RESULTS: The six exon and intron boundaries of ISL1 were screened for genetic variants in a cohort of 454 index cases. Eleven exonic variants were identified in HCM, DCM, ARVC, and/or EDMD. Out of the five novel variants, two are located in the 5'-untranslated region, two are silent (p.Arg171Arg and p.Asn189Asn), and one is a missense (p.Asn252Ser). The latter was identified in the homozygous state in one DCM patient, and in the heterozygous state in 11 relatives, who did not present with DCM but often with cardiovascular features. This variant was found in one HCM patient also carrying a MYH7 mutation and in 3/96 North-African Caucasian control individuals, but was absent in 138 European Caucasian control individuals. We investigated the effect of the ISL1 wild type and p.Asn252Ser mutant on myocyte enhancer factor 2C (Mef2c) promoter activity, an established ISL1 target. Mef2c promoter activity was ∼4-fold higher in the presence of wild-type and ∼6-fold higher in the presence of mutant ISL1 in both HEK and CHO cells.CONCLUSION: This study describes a new gain-of-function p.Asn252Ser variant in the human ISL1 gene, which could potentially lead to greater activation of downstream targets involved in cardiac development, dilation, and hypertrophy.
KW - 5' Untranslated Regions
KW - Adult
KW - Animals
KW - Arrhythmogenic Right Ventricular Dysplasia
KW - CHO Cells
KW - Cardiomyopathies
KW - Cardiomyopathy, Dilated
KW - Cardiomyopathy, Hypertrophic
KW - Case-Control Studies
KW - Cohort Studies
KW - Cricetinae
KW - Cricetulus
KW - Exons
KW - Female
KW - Gene Transfer Techniques
KW - Genetic Predisposition to Disease
KW - HEK293 Cells
KW - Heterozygote
KW - Homozygote
KW - Humans
KW - Introns
KW - LIM-Homeodomain Proteins
KW - MADS Domain Proteins
KW - MEF2 Transcription Factors
KW - Male
KW - Muscular Dystrophy, Emery-Dreifuss
KW - Mutation, Missense
KW - Myogenic Regulatory Factors
KW - Pedigree
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Transcription Factors
U2 - 10.1093/eurjhf/hfs178
DO - 10.1093/eurjhf/hfs178
M3 - SCORING: Journal article
C2 - 23152444
VL - 15
SP - 267
EP - 276
JO - EUR J HEART FAIL
JF - EUR J HEART FAIL
SN - 1388-9842
IS - 3
ER -