Abstract
Noonan syndrome (NS) and LEOPARD syndrome (LS) cause congenital afflictions such as short stature, hypertelorism and heart defects. More than 50% of NS and almost all of LS cases are caused by activating and inactivating mutations of the phosphatase Shp2, respectively. How these biochemically opposing mutations lead to similar clinical outcomes is not clear. Using zebrafish models of NS and LS and mass spectrometry-based phosphotyrosine proteomics, we identified a down-regulated peptide of Fer kinase in both NS and LS. Further investigation showed a role for Fer during development, where morpholino-based knockdown caused craniofacial defects, heart edema and short stature. During gastrulation, loss of Fer caused convergence and extension defects without affecting cell fate. Moreover, Fer knockdown cooperated with NS and LS, but not wild type Shp2 to induce developmental defects, suggesting a role for Fer in the pathogenesis of both NS and LS.
Highlights
Noonan syndrome (NS) (OMIM 163950) is a congenital disorder that manifests itself in heart defects, short stature, webbed neck, hypertelorism and an increase in the occurrence of juvenile myelomonocytic leukemia (JMML) and other malignancies
Using a comparative phosphoproteomics approach focused on pTyr-containing proteins, we identified a phosphopeptide corresponding to Fer kinase as the main decreased phosphopeptide in zebrafish embryos expressing NS or LEOPARD syndrome (LS) mutant Shp2 compared to WT
Fer knockdown induced developmental defects in zebrafish embryos that are reminiscent of defects induced by NS and LS Shp2
Summary
Noonan syndrome (NS) (OMIM 163950) is a congenital disorder that manifests itself in heart defects, short stature, webbed neck, hypertelorism and an increase in the occurrence of juvenile myelomonocytic leukemia (JMML) and other malignancies. The most common causes for NS are mutations in PTPN11 encoding for Src-homology domain 2 (SH2) containing phosphatase 2 (Shp2) [1] A similar syndrome is caused by mutations in PTPN11 and patients display similar symptoms as NS. An acronym of the symptoms, Lentigines, Electrocardiographic conduction anomalies, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth and Deafness gave this syndrome its name, LEOPARD syndrome (LS)(OMIM 151100) [1]. Both NS and LS are part of a group of congenital syndromes caused by mutations in the RAS mitogen activated protein kinase (MAPK) pathway called RASopathies. A gain-of-function for LS has been described in Drosophila [4]
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