Lauren Weiss and Erik Ullian report on two studies using carrier-derived iPSC neurons to elucidate cellular phenotypes associated with 16p11.2 CNVs and a BRAF RASopathy mutation.
Lauren Weiss and colleagues used a reverse pathway genetic approach, focused on the RAS/MAPK pathway, to show that gene-gene interactions contribute to autism.
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 her colleagues used a ‘pathway’ approach — looking at a group of genes connected in a defined biological pathway — to investigate the role of the RAS/MAPK signaling pathway in autism traits. This pathway controls many cellular functions. The researchers compared a large sample representing individuals with RASopathies — genetic, developmental disorders caused by mutations activating the RAS/MAPK pathway — with unaffected siblings and individuals with autism.
Dysregulation of the intracellular signaling pathway RAS, a risk factor for idiopathic autism, may provide a unifying theory of the disorder. Although this is not an altogether new hypothesis, several new findings have strengthened the evidence for it considerably.