De novo mutations in PLXND1 and REV3L cause Möbius syndrome

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.

Homozygous HOXB1 loss‐of‐function mutation in a large family with hereditary congenital facial paresis

“…According to the diagnostic criteria for classic MBS, all affected individuals of the Moroccan family reported here were initially misdiagnosed as having MBS [Mackinnon et al, 2014]. Although one causative gene has yet been identified for HCFP [Webb et al, 2012] and two for MBS [Tomas-Roca et al, 2015], the majority of patients with MBS or HCFP failed to get a molecular genetic diagnosis to date [Mackinnon et al, 2014;Tomas-Roca et al, 2015]. Indeed, only 1% of individuals with HCFP with or without additional clinical features were found to carry a HOXB1 mutation [Uyguner et al, 2015], implying genetic heterogeneity.…”

“…REV3L is the catalytic subunit of DNA polymerase zeta required for mutagenic replication of damaged DNA [Makarova and Burgers, 2015]. Although the two proteins are implicated in completely different pathways, deficiency of each of the two genes in mice causes hypoplasia of the facial motor nucleus [Tomas-Roca et al, 2015]. Similarly, in Hoxb1 knockout mice the facial branchiomotor (FBM) nucleus is reduced in size or completely absent and there is reduction in the motor component of the facial nerve [Goddard et al, 1996;Studer et al, 1996;Arenkiel et al, 2004].…”

“…Similarly, in Hoxb1 knockout mice the facial branchiomotor (FBM) nucleus is reduced in size or completely absent and there is reduction in the motor component of the facial nerve [Goddard et al, 1996;Studer et al, 1996;Arenkiel et al, 2004]. While Hoxb1 functions in the formation and maintenance of FBM neuron circuitry [Arenkiel et al, 2004], PLXND1 and REV3L regulate motor neuron migration and proliferation at the FBM nucleus, respectively [Tomas-Roca et al, 2015]. These data show that mutations in the three disease genes similarly disrupt motor neuron migration to the FBM nucleus.…”

“…Refinement of the minimal diagnostic criteria for MBS led to the definition of "congenital, uni-or bilateral, nonprogressive facial weakness and limited abduction of the eye(s)" [Verzijl et al, 2003;Carta et al, 2011;Mackinnon et al, 2014]. Recently, heterozygous de novo mutations in PLXND1 or REV3L have been identified in individuals with classical MBS [Tomas-Roca et al, 2015].…”

A Novel Loss-of-Function Mutation in HOXB1 Associated with Autosomal Recessive Hereditary Congenital Facial Palsy in a Large Iranian Family

“…De novo mutations in 2 genes, PLXND1 and REV3L , were recently found to be associated with MBS [Tomas-Roca et al, 2015]. Congenital facial palsy (CFP) is classified as acquired or developmental, unilateral or bilateral, and complete (palsy) or incomplete (paresis).…”