title: Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects.
abstract: Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII.
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany. posch@dhzb.de
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Posch
authors.forename: Stephan
authors.initials: S
authors.lastname: Waldmuller
authors.forename: Melanie
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheffold
authors.forename: David
authors.initials: D
authors.lastname: Fournier
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.forename: Bernard
authors.initials: B
authors.lastname: De Geeter
authors.forename: Sophie
authors.initials: S
authors.lastname: Guillaumont
authors.forename: Claire
authors.initials: C
authors.lastname: Dauphin
authors.forename: Dany
authors.initials: D
authors.lastname: Yousseff
authors.forename: Katharina R
authors.initials: KR
authors.lastname: Schmitt
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.forename: Roland
authors.initials: R
authors.lastname: Hetzer
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
authors.forename: Cemil
authors.initials: C
authors.lastname: Özcelik
mesh_terms: D000328:Adult; D024722:Cardiac Myosins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004194:Disease / Q000235:genetics*; D005190:Family; D005260:Female; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012518:Sarcomeres / Q000235:genetics* / Q000473:pathology*
chemical_list: C094239:MYH6 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains