title: Congenital valvular defects associated with deleterious mutations in thePLD1gene.
abstract: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families.
  
  
  
  Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts ofPLD1knockout mice.
  
  
  
  Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in thePLD1gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryosPLD1expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts ofPLD1knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve.
  
  
  
  The findings support a role for PLD1 in normal heart valvulogenesis.
authors: Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.|Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Asaf
authors: A
authors: Ta-Shma
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
authors: Kai
authors: K
authors: Zhang
authors: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors: Ekaterina
authors: E
authors: Salimova
authors: Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
authors: Alma
authors: A
authors: Zernecke
authors: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors: Daniel
authors: D
authors: Sieiro-Mosti
authors: Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
authors: David
authors: D
authors: Stegner
authors: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors: Milena
authors: M
authors: Furtado
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Avraham
authors: A
authors: Shaag
authors: Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Zeev
authors: Z
authors: Perles
authors: Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
authors: Bernhard
authors: B
authors: Nieswandt
authors: Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Azaria J J T
authors: AJ
authors: Rein
authors: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors: Nadia
authors: N
authors: Rosenthal
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
authors: Aaron M
authors: AM
authors: Neiman
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Orly
authors: O
authors: Elpeleg
mesh_terms: D000818:Animals; D002642:Chick Embryo; D004452:Echocardiography; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008945:Mitral Valve Prolapse / Q000235:genetics* / Q000503:physiopathology; D009232:Myxoma / Q000235:genetics* / Q000503:physiopathology; D010739:Phospholipase D / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D010739:Phospholipase D; C106801:phospholipase D1
keywords: Congenital heart defects