title: CCN1 mutation is associated with atrial septal defect.
abstract: The genetic basis of congenital heart disease remains unknown in most of the cases. Recently, a novel mouse model shed new light on the role of CCN1/CYR61, a matricellular regulatory factor, in cardiac morphogenesis. In a candidate gene approach, we analyzed a cohort of 143 patients with atrial septal defects (ASD) by sequencing the coding exons of CCN1. In addition to three frequent polymorphisms, we identified an extremely rare novel heterozygous missense mutation (c.139C > T; p.R47W) in one patient with severe ASD. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the N-terminal insulin-like growth factor binding protein module. Further bioinformatic analysis, exclusion of known ASD disease genes as well as the exclusion of the mutation in a very high number of ethnically matched controls (more than 1,000 individuals) and in public genetic databases, indicates that the p.R47W variant is a probable disease-associated mutation. The report about ASD in mice in heterozygous Ccn 1 +/- animals strongly supports this notion. Our study is the first to suggest a relationship between a probable CCN1 mutation and ASD. Our purpose here was to draw attention to CCN1, a gene that we believe may be important for genetic analysis in patients with congenital heart disease.
authors.affiliation: Cardiovascular Genetics, Experimental & Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany, andreas.perrot@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Katharina R
authors.initials: KR
authors.lastname: Schmitt
authors.forename: Eva-Maria G
authors.initials: EM
authors.lastname: Roth
authors.forename: Brigitte
authors.initials: B
authors.lastname: Stiller
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Posch
authors.forename: Edmund N L
authors.initials: EN
authors.lastname: Browne
authors.forename: Christian
authors.initials: C
authors.lastname: Timmann
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.forename: Cemil
authors.initials: C
authors.lastname: Özcelik
mesh_terms: D000328:Adult; D055515:Cysteine-Rich Protein 61 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006344:Heart Septal Defects, Atrial / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014463:Ultrasonography
chemical_list: C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61