Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases. [Display omitted] •Mast1 associates with the microtubule cytoskeleton in a MAP-dependent manner•Mast1 is expressed in postmitotic neurons but not neuronal progenitors•Mast1 Leu278del mice have an enlarged corpus callosum and smaller cerebellum•More axons cross the midline in Mast1 Leu278del mice despite cortical apoptosis Tripathy et al. show that mutations in MAST1, a microtubule-associated protein, cause a syndrome characterized by an enlarged corpus callosum. They attribute this thickening to an increase in the number of contralateral projections despite extensive cortical apoptosis.