Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Cell Signaling

Background:

• The RAF-MEK-ERK pathway (MAPK cascade) is crucial for cellular processes and development.
• Aberrant signaling in this pathway contributes to cancer and RASopathies.
• RASopathies are a group of cancer-prone genetic disorders.

Purpose of the Study:

• To investigate the role of MAPK1 gene variants in neurodevelopmental disorders.
• To understand the functional consequences of MAPK1 mutations within the RASopathy spectrum.
• To elucidate the molecular mechanisms underlying MAPK1-associated diseases.

Main Methods:

• Analysis of de novo missense variants in the MAPK1 gene.
• In vitro and in vivo studies to assess kinase phosphorylation and nuclear translocation.
• Investigation of interactions between MAPK1 variants and regulatory proteins like MKP3.

Main Results:

• De novo missense variants in MAPK1 cause a neurodevelopmental disease within the RASopathy spectrum.
• Pathogenic variants lead to increased ERK2 phosphorylation, nuclear translocation, and enhanced signaling.
• Two classes of variants were identified, one disrupting MKP3 binding.
• Signal dysregulation is stimulus-dependent and MEK-dependent.

Conclusions:

• Pathogenic MAPK1 variants contribute to RASopathies, including conditions resembling Noonan syndrome.
• Variants have counteracting effects on MAPK1 function, impacting regulator and substrate interactions.
• These findings expand the genetic landscape of RASopathies and highlight the MAPK cascade's role.