Copy number variants (CNVs) are the regions of the human genome that represent significant genetic risk factors for autism and other neurodevelopmental disorders. One such CNV located on chromosome 16, called 16p11.2, confers a high risk for developing autism and intellectual disability when deleted, and autism, schizophrenia, bipolar disorder and intellectual disability when duplicated. Even more intriguingly, 16p11.2 deletions are associated with increased head and brain size in the carriers (macrocephaly), whereas 16p11.2 duplications are associated with the decreased head and brain size (microcephaly). However, the exact mechanism by which this CNV influences brain size is unknown.

Recent work in Lilia Iakoucheva’s laboratory at the University of California, San Diego gave some clues to what this mechanism might be. The researchers have demonstrated that interaction between two proteins, KCTD13, located within the 16p11.2 CNV, and CUL3, located on chromosome 2, influences the level of a third protein, RhoA¹. This three-protein complex may be important for regulating brain size during fetal development. RhoA is already known to be involved in cell migration and cell-to-cell communication, and 16p11.2 CNV may be a major regulator of RhoA levels.

In a collaborative study, Lilia Iakoucheva and Alysson Muotri propose to test this hypothesis using skin fibroblasts from individuals with autism who have the 16p11.2 CNV. Fibroblasts will be differentiated into neurons and, using sequencing and other modern genomics approaches, will be used to investigate molecular changes related to alterations in RhoA levels. The team will also test RhoA inhibitors as potential candidate autism therapeutics. Gaining precise knowledge of the pathway(s) disrupted by the 16p11.2 CNV is of key importance for developing better drug targets for the treatment of autism and other disorders linked to this CNV.