Understanding Molecular Basis of PTPN11-Related Diseases

Area of Science:

• Genetics and Molecular Biology
• Biochemistry
• Medical Genetics

Background:

• The PTPN11 gene encodes SHP2 phosphatase, a crucial regulator of cellular processes via signaling pathways like RAS/MAPK.
• Missense variants in PTPN11 are linked to developmental disorders including Noonan syndrome (NS), LEOPARD syndrome (LS), and juvenile myelomonocytic leukemia (JMML).
• These variants can result in altered SHP2 catalytic activity, leading to both loss-of-function (LOF) and gain-of-function (GOF) molecular and phenotypic effects.

Purpose of the Study:

• To elucidate the molecular mechanisms differentiating the pathogenicity of PTPN11 missense variants.
• To predict the structural impacts of PTPN11 variants using computational tools.
• To correlate variant characteristics with clinical outcomes, particularly in NS.

Main Methods:

• Utilized MutPred2 and AlphaFold2 for predicting structural consequences of PTPN11 missense variants.
• Analyzed functional mechanisms, including sodium and DNA binding, for LOF and GOF variants.
• Correlated variant pathogenicity with clinical data from fetuses with ultrasound anomalies and familial cases.

Main Results:

• Identified distinct functional mechanisms for LOF and GOF PTPN11 variants concerning sodium and DNA binding.
• Predicted structural consequences of missense substitutions impacting SHP2 inter-domain regulation and phosphatase activity.
• Found that NS-associated variants in fetuses with ultrasound anomalies and familial cases are more frequently pathogenic.

Conclusions:

• PTPN11 missense variants exhibit diverse pathogenicity based on their impact on SHP2 function and structure.
• Computational prediction tools aid in understanding the molecular basis of variant effects.
• Early identification of pathogenic PTPN11 variants, especially in at-risk fetal populations, is crucial for diagnosis and management of associated syndromes.