The Ras/MAPK pathway is central for brain development and function. In children, genetic mutations affecting the Ras/MAPK pathway lead to multiple disorders with cognitive-behavioral phenotypes, collectively termed ?RASopathies? (e.g. Noonan syndrome, neurofibromatosis 1, Costello syndrome). As a collection of conditions, RASopathies are common genetic disorders (1:1,000), and Noonan syndrome (NS) is the most common of these conditions (1:2,000). There is strong empirical support that NS affects cognition and behavior, particularly increasing risk for behaviors associated with ADHD, and impairments in executive function and social skills. Further, data collected from animal models of NS show significant effects on brain development, brain function and behavior. Yet, in the face of these notable findings, no systematic investigation of early human brain development in NS has been conducted to date. Thus, major gaps exist in understanding how NS increases risk for suboptimal cognitive-behavioral outcome in children. The proposed research is designed to define the effects of NS on brain anatomy and connectivity. Our hypothesis is that Ras/MAPK mutations in NS are associated with neural correlates implicated in attention and social skills. Our sample will include 40 girls with NS seen at 5-11 years of age compared to 40 sex- and age- matched typically developing controls and to a (clinical) group of 40 age-matched girls with Turner syndrome. Using high-resolution structural MRI, diffusion-weighted imaging, resting state fMRI, and a targeted battery of cognitive-behavioral assessments, we will first assess the neural correlates of, and cognitive-behavioral features associated with attentional and social dysfunction in girls with NS relative to controls. Second, we will explore associations between brain imaging profiles and specific NS Ras/MAPK mutations (PTPN11 or SOS1). The rationale for the proposed project is that defining the neural correlates in NS will improve our ability to understand how neural variations associated with the Ras/MAPK pathway affect attention and cognitive processes in humans. With respect to outcome, examining this population will provide important insights into the effects of the Ras/MAPK pathway on brain structure and connectivity. In addition the proposed research holds promise for providing novel brain-based outcome measures for future clinical interventions in NS. For example, medication decreasing activation in the Ras/MAPK pathway (enhanced in NS) already has showed beneficial effects on learning in mouse models of NS. Finally, the results generated from our study will significantly contribute to a broader understanding of the Ras/MAPK as a central biological mechanism contributing to ADHD and learning in children.

Public Health Relevance

The Ras/MAPK pathway is central to brain development and function in humans. Noonan syndrome (1:2,000), is a developmental syndrome associated with genetic mutations affecting the Ras/MAPK pathway. Children with Noonan syndrome are commonly diagnosed with ADHDand they have impaired social skills. Since major gaps exist in understanding how Noonan syndrome increases risk for these deficits, we propose to examine differences in brain structure and connectivity in children with this important condition.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Griffin, James
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Stanford University
Schools of Medicine
United States
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Johnson, Emily M; Ishak, Alexandra D; Naylor, Paige E et al. (2018) PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention. Cereb Cortex :