De novo mutations in PLXND1 and REV3L cause Mobius syndrome

Abstract

Mo ̈bius syndrome (MBS) is a neurological disorder that is characterized by paralysis of thefacial nerves and variable other congenital anomalies. The aetiology of this syndrome hasbeen enigmatic since the initial descriptions by von Graefe in 1880 and by Mo ̈bius in 1888,and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology.Here, we reportde novomutations affecting two genes,PLXND1andREV3Lin MBS patients.PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development:neural migration and DNA translesion synthesis, essential for the replication of endogenouslydamaged DNA, respectively. Interestingly, analysis ofPlxnd1andRev3lmutant mice showsthat disruption of these separate pathways converge at the facial branchiomotor nucleus,affecting either motoneuron migration or proliferation. The finding thatPLXND1andREV3Lmutations are responsible for a proportion of MBS patients suggests thatde novomutations inother genes might account for other MBS patients