Abstract
Möbius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Möbius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients.
Highlights
Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies
This is in contrast to hereditary congenital facial palsy (HCFP), which is characterized by the isolated dysfunction of the facial nerve
The present data establish de novo mutations as a cause for MBS, providing a rationale for exome sequencing in patient–parent trios to identify de novo mutations in other genes underlying MBS
Summary
Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. Mobius syndrome (MBS) (MIM 157900) is a rare congenital cranial dysinnervation disorder characterized by non-progressive facial palsy and impairment of ocular abduction, due to paralysis or weakness of the facial (n7) and abducens (n6) nerves, and frequently other cranial nerves[1,2,3,4,5,6] Both intrauterine environmental factors and genetic causes have been proposed for the aetiology and pathogenesis of MBS. The causality of de novo PLXND1 and REV3L mutations for the neuropathological features of MBS is further supported by analysis of the respective knockout mice For both heterozygous mutants we observe hypoplasia of the facial branchiomotor nucleus, which is consistent with the facial nerve weakness in MBS patients. The present data establish de novo mutations as a cause for MBS, providing a rationale for exome sequencing in patient–parent trios to identify de novo mutations in other genes underlying MBS
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