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PTPN11 mutations play a minor role in isolated congenital heart disease

Weismann, Constance G LU ; Hager, A ; Kaemmerer, H ; Maslen, C L ; Morris, Cynthia D ; Schranz, D ; Kreuder, J and Gelb, B D (2005) In American Journal of Medical Genetics. Part A 136A(2). p.51-146
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... (More)

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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keywords
Adolescent, Adult, Aortic Coarctation/genetics, Base Sequence, Chromatography, High Pressure Liquid/methods, DNA/chemistry, DNA Mutational Analysis, Female, Heart Defects, Congenital/genetics, Heart Septal Defects, Atrial/genetics, Heart Septal Defects, Ventricular/genetics, Humans, Intracellular Signaling Peptides and Proteins/chemistry, Introns/genetics, Male, Mutation, Polymorphism, Genetic, Protein Conformation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases/chemistry
in
American Journal of Medical Genetics. Part A
volume
136A
issue
2
pages
6 pages
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:22044444972
  • pmid:15940693
ISSN
1552-4825
DOI
10.1002/ajmg.a.30789
language
English
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no
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1c40666e-66be-4460-86e5-e7e72eba7a1f
date added to LUP
2019-01-25 14:47:59
date last changed
2020-06-10 05:53:40
@article{1c40666e-66be-4460-86e5-e7e72eba7a1f,
  abstract     = {<p>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 &gt; 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 &gt; 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.</p>},
  author       = {Weismann, Constance G and Hager, A and Kaemmerer, H and Maslen, C L and Morris, Cynthia D and Schranz, D and Kreuder, J and Gelb, B D},
  issn         = {1552-4825},
  language     = {eng},
  month        = {07},
  number       = {2},
  pages        = {51--146},
  publisher    = {John Wiley and Sons Inc.},
  series       = {American Journal of Medical Genetics. Part A},
  title        = {PTPN11 mutations play a minor role in isolated congenital heart disease},
  url          = {http://dx.doi.org/10.1002/ajmg.a.30789},
  doi          = {10.1002/ajmg.a.30789},
  volume       = {136A},
  year         = {2005},
}