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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

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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, Vol. 15, No. 3, 01.03.2013, p. 267-76.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Friedrich, FW, Dilanian, G, Khattar, P, Juhr, D, Gueneau, L, Charron, P, Fressart, V, Vilquin, J-T, Isnard, R, Gouya, L, Richard, P, Hammoudi, N, Komajda, M, Bonne, G, Eschenhagen, T, Dubourg, O, Villard, E & Carrier, L 2013, 'A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity', EUR J HEART FAIL, vol. 15, no. 3, pp. 267-76. https://doi.org/10.1093/eurjhf/hfs178

APA

Friedrich, F. W., Dilanian, G., Khattar, P., Juhr, D., Gueneau, L., Charron, P., Fressart, V., Vilquin, J-T., Isnard, R., Gouya, L., Richard, P., Hammoudi, N., Komajda, M., Bonne, G., Eschenhagen, T., Dubourg, O., Villard, E., & Carrier, L. (2013). A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity. EUR J HEART FAIL, 15(3), 267-76. https://doi.org/10.1093/eurjhf/hfs178

Vancouver

Friedrich FW, Dilanian G, Khattar P, Juhr D, Gueneau L, Charron P et al. A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity. EUR J HEART FAIL. 2013 Mar 1;15(3):267-76. https://doi.org/10.1093/eurjhf/hfs178

Bibtex

@article{f8cd3be0593c432baf46c7540a99169d,
title = "A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity",
abstract = "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.",
keywords = "5' Untranslated Regions, Adult, Animals, Arrhythmogenic Right Ventricular Dysplasia, CHO Cells, Cardiomyopathies, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Case-Control Studies, Cohort Studies, Cricetinae, Cricetulus, Exons, Female, Gene Transfer Techniques, Genetic Predisposition to Disease, HEK293 Cells, Heterozygote, Homozygote, Humans, Introns, LIM-Homeodomain Proteins, MADS Domain Proteins, MEF2 Transcription Factors, Male, Muscular Dystrophy, Emery-Dreifuss, Mutation, Missense, Myogenic Regulatory Factors, Pedigree, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription Factors",
author = "Friedrich, {Felix W} and Gilles Dilanian and Patricia Khattar and Denise Juhr and Lucie Gueneau and Philippe Charron and V{\'e}ronique Fressart and Jean-Thomas Vilquin and Richard Isnard and Laurent Gouya and Pascale Richard and Naima Hammoudi and Michel Komajda and Gis{\`e}le Bonne and Thomas Eschenhagen and Olivier Dubourg and Eric Villard and Lucie Carrier",
year = "2013",
month = mar,
day = "1",
doi = "10.1093/eurjhf/hfs178",
language = "English",
volume = "15",
pages = "267--76",
journal = "EUR J HEART FAIL",
issn = "1388-9842",
publisher = "Oxford University Press",
number = "3",

}

RIS

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 -