title: On the role of the gap junction protein Cx43 (GJA1) in human cardiac malformations with Fallot-pathology. a study on paediatric cardiac specimen.
abstract: BACKGROUND
  Gap junction channels are involved in growth and differentiation. Therefore, we wanted to elucidate if the main cardiac gap junction protein connexin43 (GJA1) is altered in patients with Tetralogy of Fallot or double-outlet right ventricle of Fallot-type (62 patients referred to as Fallot) compared to other cardiac anomalies (21 patients referred to as non-Fallot). Patients were divided into three age groups: 0-2years, 2-12years and >12years. Myocardial tissue samples were collected during corrective surgery and analysis of cell morphology, GJA1- and N-cadherin (CDH2)-distribution, as well as GJA1 protein- and mRNA-expression was carried out. Moreover, GJA1-gene analysis of 16 patients and 20 healthy subjects was performed.
  
  
  RESULTS
  Myocardial cell length and width were significantly increased in the oldest age group compared to the younger ones. GJA1 distribution changed significantly during maturation with the ratio of polar/lateral GJA1 increasing from 2.93±0.68 to 8.52±1.41. While in 0-2years old patients ∼6% of the lateral GJA1 was co-localised with CDH2 this decreased with age. Furthermore, the changes in cell morphology and GJA1-distribution were not due to the heart defect itself but were significantly dependent on age. Total GJA1 protein expression decreased during growing-up, whereas GJA1-mRNA remained unchanged. Sequencing of the GJA1-gene revealed only few heterozygous single nucleotide polymorphisms within the Fallot and the healthy control group.
  
  
  CONCLUSIONS
  During maturation significant changes in gap junction remodelling occur which might be necessary for the growing and developing heart. In our study point mutations within the Cx43-gene could not be identified as a cause of the development of TOF.
authors.affiliation: Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Aida
authors.initials: A
authors.lastname: Salameh
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Josphina
authors.initials: J
authors.lastname: Haunschild
authors.affiliation: Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Bräuchle
authors.affiliation: Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peim
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidel
authors.affiliation: Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Reitmann
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kostelka
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Farhad
authors.initials: F
authors.lastname: Bakhtiary
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dhein
authors.affiliation: Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Dähnert
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D018031:Connexin 43 / Q000378:metabolism*; D004310:Double Outlet Right Ventricle / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D013771:Tetralogy of Fallot / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
chemical_list: D018031:Connexin 43
references.citation: Circ Res. 1986 Mar;58(3):356-71
references.pmid: 3719925
references.citation: Circ Res. 1997 Jan;80(1):88-94
references.pmid: 8978327
references.citation: J Cardiovasc Dis Res. 2011 Oct;2(4):206-12
references.pmid: 22135478
references.citation: Hypertension. 1995 Dec;26(6 Pt 1):979-83
references.pmid: 7490158
references.citation: J Cardiovasc Electrophysiol. 1994 Feb;5(2):182-209
references.pmid: 8186887
references.citation: Nat Protoc. 2011 Nov 10;6(12):1929-41
references.pmid: 22082987
references.citation: Cardiovasc Res. 1999 May;42(2):309-17
references.pmid: 10533569
references.citation: Circ Res. 2010 May 28;106(10):1592-602
references.pmid: 20378856
references.citation: Circ Res. 1979 Feb;44(2):250-62
references.pmid: 761307
references.citation: Virchows Arch Pathol Anat Physiol Klin Med. 1953;323(2):223-42
references.pmid: 13078214
references.citation: J Mol Cell Cardiol. 2008 Mar;44(3):597-606
references.pmid: 18201716
references.citation: Science. 1995 Mar 24;267(5205):1831-4
references.pmid: 7892609
references.citation: Magn Reson Med. 2013 Jun;69(6):1595-602
references.pmid: 22826018
references.citation: J Mol Cell Cardiol. 2001 Feb;33(2):359-71
references.pmid: 11162139
references.citation: Circ Res. 1974 Aug;35(2):suppl II:17-26
references.pmid: 4276486
references.citation: J Cell Biol. 1991 Dec;115(5):1357-74
references.pmid: 1659577
references.citation: Ann Biomed Eng. 2011 Nov;39(11):2683-94
references.pmid: 21822740
references.citation: Biophys J. 2010 Nov 3;99(9):2821-30
references.pmid: 21044579
references.citation: J Am Coll Cardiol. 1992 Mar 1;19(3):619-29
references.pmid: 1538019
references.citation: Heart Vessels. 1991;6(3):129-42
references.pmid: 1833369
references.citation: Heart. 1996 Nov;76(5):412-7
references.pmid: 8944586
references.citation: Ann Thorac Surg. 2000 Apr;69(4 Suppl):S249-63
references.pmid: 10798433
references.citation: Methods. 2010 Apr;50(4):250-61
references.pmid: 20085814
references.citation: Br J Pharmacol. 2009 Sep;158(1):198-208
references.pmid: 19719782
references.citation: Jpn Circ J. 1986 Oct;50(10):1023-32
references.pmid: 3806926
references.citation: Anat Embryol (Berl). 1992;185(4):363-78
references.pmid: 1319120
references.citation: Circulation. 2012 May 29;125(21):2578-87
references.pmid: 22523313
references.citation: Pediatr Res. 1994 Nov;36(5):561-6
references.pmid: 7877871
references.citation: Cardiovasc Res. 2004 May 1;62(2):426-36
references.pmid: 15094362
references.citation: N Engl J Med. 1995 May 18;332(20):1323-9
references.pmid: 7715640
references.citation: Biochem J. 2007 Dec 15;408(3):375-85
references.pmid: 17714073
references.citation: Am J Cardiovasc Pathol. 1990;3(1):5-11
references.pmid: 2331361
references.citation: Circ Res. 1989 Mar;64(3):501-14
references.pmid: 2465097
references.citation: Circ Res. 1988 Apr;62(4):811-32
references.pmid: 2450697
references.citation: Front Pharmacol. 2013 Jun 03;4:70
references.pmid: 23760510
references.citation: Mol Cell Biochem. 2003 Jan;242(1-2):121-7
references.pmid: 12619874
references.citation: Circulation. 1994 Aug;90(2):713-25
references.pmid: 8044940