Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

Sci Signal. 2018 Mar 20;11(522):eaao1591. doi: 10.1126/scisignal.aao1591.


Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell-specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biocatalysis
  • Ependyma / cytology
  • Ependyma / metabolism
  • Gain of Function Mutation*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Hydrocephalus / genetics*
  • Hydrocephalus / metabolism
  • LEOPARD Syndrome / genetics*
  • LEOPARD Syndrome / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Stem Cells / metabolism
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism


  • Protein Tyrosine Phosphatase, Non-Receptor Type 11