A recurrent MCF2 variant which disrupts DCC binding leads to congenital mirror movements and corpus callosum agenesis

Abstract Neuronal wiring in the developing nervous system relies on axon guidance, a process which enables proper axon pathfinding to target cells. Disruption of axon guidance results in a wide spectrum of defects including congenital mirror movements (CMM) and corpus callosum agenesis (CCA). Axon guidance signaling pathways, such as Netrin-1/DCC, act through guanine nucleotide exchange factors (GEFs) to activate Rho GTPases, which regulate axon outgrowth and pathfinding. MCF2 is an X-linked gene that encodes a GEF which activates the GTPases Rac1 and Cdc42. We identify a recurrent hemizygous MCF2 variant [NM_001171876.2: c.31C > T p.(R11W)] in two unrelated cases displaying axon guidance and corticospinal defects: an adult male with CMM and an unrelated male fetus with CCA and abnormal corticospinal tract decussation on autopsy. Through biochemical and cellular studies, we demonstrate that MCF2 interacts physically with DCC and is able to induce DCC subcellular relocalization. The MCF2 p.(R11W) variant disrupts the interaction with DCC, is less efficient at relocalizing DCC, and has decreased GEF activity. Together, our results link an MCF2 variant to axon guidance defects in humans. Furthermore, our data suggests that this MCF2 variant may impair axon guidance by impacting DCC signaling, a key regulator of commissural and corticospinal axon guidance.