title: A novel genetic variant in the transcription factor Islet-1 exerts gain of function on myocyte enhancer factor 2C promoter activity.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Felix W
authors.initials: FW
authors.lastname: Friedrich
authors.forename: Gilles
authors.initials: G
authors.lastname: Dilanian
authors.forename: Patricia
authors.initials: P
authors.lastname: Khattar
authors.forename: Denise
authors.initials: D
authors.lastname: Juhr
authors.forename: Lucie
authors.initials: L
authors.lastname: Gueneau
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Jean-Thomas
authors.initials: JT
authors.lastname: Vilquin
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Naima
authors.initials: N
authors.lastname: Hammoudi
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubourg
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics; D016466:CHO Cells; D009202:Cardiomyopathies / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D006224:Cricetinae; D003412:Cricetulus; D005091:Exons; D005260:Female; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D026161:MADS Domain Proteins / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008297:Male; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics*; D020125:Mutation, Missense; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D060850:LIM-Homeodomain Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1