PTPN11 mutations play a minor role in isolated congenital heart disease

Constance G. Weismann, A. Hager, H. Kaemmerer, Cheryl Maslen, Cynthia Morris, D. Schranz, J. Kreuder, B. D. Gelb

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)146-151
Number of pages6
JournalAmerican Journal of Medical Genetics
Volume136 A
Issue number2
DOIs
StatePublished - Jul 15 2005

Fingerprint

Heart Diseases
Noonan Syndrome
Mutation
Phosphotyrosine
Aortic Coarctation
Exons
Pulmonary Valve Stenosis
src Homology Domains
Congenital Heart Defects
Hypertrophic Cardiomyopathy
Missense Mutation
Introns
High Pressure Liquid Chromatography
Atrioventricular Septal Defect
Proteins

Keywords

  • Aortic coarctation
  • Atrioventricular canal
  • Atrioventricular septal defect
  • Coarctation
  • Coarctation of the aorta
  • Congenital heart defect
  • Congenital heart disease
  • Noonan syndrome
  • Protein tyrosine phosphatase
  • PTPN11
  • SHP-2
  • SHP2
  • Src homology 2

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

PTPN11 mutations play a minor role in isolated congenital heart disease. / Weismann, Constance G.; Hager, A.; Kaemmerer, H.; Maslen, Cheryl; Morris, Cynthia; Schranz, D.; Kreuder, J.; Gelb, B. D.

In: American Journal of Medical Genetics, Vol. 136 A, No. 2, 15.07.2005, p. 146-151.

Research output: Contribution to journalArticle

Weismann, CG, Hager, A, Kaemmerer, H, Maslen, C, Morris, C, Schranz, D, Kreuder, J & Gelb, BD 2005, 'PTPN11 mutations play a minor role in isolated congenital heart disease', American Journal of Medical Genetics, vol. 136 A, no. 2, pp. 146-151. https://doi.org/10.1002/ajmg.a.30789
Weismann, Constance G. ; Hager, A. ; Kaemmerer, H. ; Maslen, Cheryl ; Morris, Cynthia ; Schranz, D. ; Kreuder, J. ; Gelb, B. D. / PTPN11 mutations play a minor role in isolated congenital heart disease. In: American Journal of Medical Genetics. 2005 ; Vol. 136 A, No. 2. pp. 146-151.
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abstract = "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.",
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AB - 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.

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