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GENATLAS PHENOTYPE
last update : 12-07-2013
Symbol NS1
Location 12q24.13
Name Noonan syndrome 1
Other name(s)
  • male Turner syndrome
  • female pseudo-turner syndrome
  • Turner phenotype with normal karyotype
    • Corresponding gene PTPN11
    Other symbol(s) NNS1
    Main clinical features
  • typical heart defect, either pulmonary stenosis or cardiomyopathy, typical craniofacial anomalies including hypertelorism, downward slant of palpebral fissures and ptosis, short and webbed neck, high prevalences of patent ductus
    • arteriosus and thrombocytopenia
  • others : short stature, mild mental retardation or speech delay, bleeding diathesis, thorax deformity, cubitus valgus, low-set ears, low posterior hairline, cryptorchidism
    • Genetic determination autosomal dominant
    Prevalence 50 p100 of all Noonan syndrome
    Related entries . including Noonan-like syndrome with giant-cell lesion syndrome . related phenotype : Cardio faciocutaneous syndrome (CFC), Costello syndrome (COSTS)
    Function/system disorder cardiovascular
    multisystem/generalized
    Type malformation
    Gene product
    Name protein tyrosine phosphatase non receptor type11
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense   abnormal protein/gain of function mostly in N-SH2 and PTP domains (exons 3, 8, 13), accounting for 50p100 of cases, higher prevalence in familial cases, with distorted ratio in the sex of subjects with sporadic form and PTPN11 mutations and paternal origin (advanced paternal age)
    various types   abnormal protein/gain of function enhancing frequency of cardiomyocyte Ca2+ oscillations, correlated with reduced nuclear translocation and transcriptional activity of NFATC1 and disrupting the Ca2+ oscillatory control of NFATC1, suggesting a potential mechanism for congenital heart defects
    deletion     resulting in the removal of Aspartate 61 (D61del), a key residue of the N-terminal SH2, playing a major role for proper down-regulation of the protein tyrosine phosphatase activity of SHP-2
    other     the most common mutation, c.922A>G, is at least 2,400 times greater than the genome average
    Remark(s) . mutations are gain-of-function, with most disrupting SHP-2s activation-inactivation mechanism and dysregulated RAS-mitogen activated protein kinase signal transduction
  • Gain of function mutations may contribute to tumorigenesis by enhancing tumor angiogenesis (Wang 2009)
  • dysregulated phosphatase activity of PTPN11, even at low level, is sufficient to cause the overlapping clinical features of LEOPS and NS1 (Oishi 2009)
  • cardiac defects in NS result from mutant PTPN11 expression in the endocardium, not in the myocardium or neural crest (Araki 2009)
  • Q79R leading to hyperactivation of MAPK1/MAPK3 and to craniofacial defects defects (Nakamura 2009)
  • NS1-causing PTPN11 mutants inhibit GH-induced IGF1 release through RAS/MAPK1/MAPK3 hyperactivation, and RAS/MAPK1/MAPK3 modulation could alleviate the short stature phenotype in NS1 caused by PTPN11 mutations (PMID: 22371576))
  • germline selection can explain in NS, Apert syndrome, and MEN2B the recurrent high mutation frequency, male mutation bias, and paternal age effect (PMID: 23726368))
    • Genotype/Phenotype correlations . presence of pulmonary stenosis, short stature, easy bruising, and thorax deformities are significantly associated with a PTPN11 mutation, whereas cardiomyopathy is more common in patients without a mutation
  • variant G409A associated to a mild form, chest deformities, mild pterygium coli variable growth delay, mild craniofacial features
  • T73I mutation in the PTPN11 gene is associated with a predisposition
    • to myeloproliferative disorder, which most often resolves spontaneously (Ko 2008)