AUTHOR=O’Neill Adam C. , Kyrousi Christina , Einsiedler Melanie , Burtscher Ingo , Drukker Micha , Markie David M. , Kirk Edwin P. , Götz Magdalena , Robertson Stephen P. , Cappello Silvia 

TITLE=Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=12

YEAR=2018

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2018.00057

DOI=10.3389/fncel.2018.00057

ISSN=1662-5102

ABSTRACT=<p>Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor—<italic>MOB2</italic>—in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of <italic>Mob2</italic> within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development.</p>