PTPN11 mutations play a minor role in isolated congenital heart disease

Am J Med Genet A. 2005 Jul 15;136(2):146-51. doi: 10.1002/ajmg.a.30789.


PTPN11 missense mutations cause approximately 50% of Noonan syndrome, an autosomal dominant disorder presenting with various congenital heart defects, most commonly valvar pulmonary stenosis, and hypertrophic cardiomyopathy. Atrioventricular septal defects and coarctation of the aorta occur in 15% and 9%, respectively. The aim of this study was to determine if PTPN11 mutations exist in non-syndromic patients with these two relevant forms of congenital heart disease. The 15 coding PTPN11 exons and their intron boundaries from subjects with atrioventricular septal defects (n = 24) and coarctation of the aorta (n = 157) were analyzed using denaturing high performance liquid chromatography and sequenced if abnormal. One subject with an atrioventricular septal defect but no other known medical problems had a c.127C > T transition in exon 2, predicting a p.L43F substitution. This mutation affected the phosphotyrosine-binding region in the N-terminal src homology 2 domain and was close to a Noonan syndrome mutation (p.T42A). An otherwise healthy patient with aortic coarctation had a silent c.540C > T change in exon 5 corresponding to p.D180D. Our study showed that PTPN11 mutations are rarely found in two isolated forms of congenital heart disease that commonly occur in Noonan syndrome. The p.L43F mutation belongs to a rare class of PTPN11 mutations altering the phosphotyrosine-binding region. These mutations are not predicted to alter the autoinhibition of the PTPN11 protein product, SHP-2, which is the mechanism for the vast majority of mutations causing Noonan syndrome. Future studies will be directed towards understanding these rare phosphotyrosine binding region mutants.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aortic Coarctation / genetics
  • Aortic Coarctation / pathology
  • Base Sequence
  • Chromatography, High Pressure Liquid / methods
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • Female
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Heart Septal Defects, Atrial / genetics
  • Heart Septal Defects, Atrial / pathology
  • Heart Septal Defects, Ventricular / genetics
  • Heart Septal Defects, Ventricular / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Introns / genetics
  • Male
  • Mutation*
  • Polymorphism, Genetic
  • Protein Conformation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / chemistry
  • Protein Tyrosine Phosphatases / genetics*


  • Intracellular Signaling Peptides and Proteins
  • DNA
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases