Although 16p11.2 copy number variants (CNVs) make a significant contribution to the risk of autism spectrum disorder (ASD) and are becoming well described at the clinical level, the biological mechanisms underlying pathogenesis are not yet understood. MAPK3, MVP and KCTD13 — three of the genes in the 16p11.2 chromosomal region — are involved in RAS/MAPK signaling, a ubiquitous signaling pathway important for proliferation, differentiation and apoptosis across development. Interestingly, there is overlap between clinical and neuroimaging presentation in individuals with a 16p11.2 CNV and those with classic RASopathy syndromes, which are caused by dominant mutations activating RAS/MAPK signaling. There is also phenotypic overlap between 16p11.2 syndrome and RASopathy model organisms. Combined, these data suggest that alterations in RAS/MAPK signaling play an important role in the 16p11.2 CNV syndrome phenotype.

Lauren Weiss and Erik Ullian from the University of California, San Francisco propose to use human induced pluripotent stem cell (iPSC) lines to identify specific 16p11.2-associated cellular phenotypes mediated by RAS/MAPK signaling. The central hypothesis is that dysregulation of MAPK3 or MVP/KCTD13 contributes to cellular features that can be isolated via comparison of iPSCs from 16p11.2 CNV individuals and iPSCs derived from individuals with a RASopathy. Preliminary data from this group have shown specific and reproducible neuronal and glial phenotypes in cells differentiated from RASopathy iPSCs.

Weiss and Ullian will use human iPSCs derived from 16p11.2 CNV individuals, as well as iPSC lines from two RASopathies — Costello syndrome (caused by mutations in HRAS) and cardio-facio-cutaneous syndrome (caused by mutations in BRAF) — to study cellular neurodevelopmental phenotypes. Given the excessive generation of astrocytes reported in mouse RASopathy models¹, the experimental approach will have a dual focus on neuronal and glial development and function, assessing morphology, functional properties, and protein and RNA expression.

Results from these studies will clarify the cellular impact of RAS/MAPK signaling on 16p11.2 CNVs, will advance our neurodevelopmental understanding of the clinical phenotype and will provide a platform for informed therapeutic intervention.