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.
Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations / Tripathy, Ratna; Leca, Ines; van Dijk, Tessa; Weiss, Janneke; van Bon, Bregje W; Sergaki, Maria Christina; Gstrein, Thomas; Breuss, Martin; Tian, Guoling; Bahi-Buisson, Nadia; Paciorkowski, Alexander R; Pagnamenta, Alistair T; Wenninger-Weinzierl, Andrea; Martinez-Reza, Maria Fernanda; Landler, Lukas; DE LISE, Stefano; Taylor, Jenny C; Terrone, Gaetano; Vitiello, Giuseppina; Del Giudice, Ennio; Brunetti-Pierri, Nicola; D'Amico, Alessandra; Reymond, Alexandre; Voisin, Norine; Bernstein, Jonathan A; Farrelly, Ellyn; Kini, Usha; Leonard, Thomas A; Valence, Stéphanie; Burglen, Lydie; Armstrong, Linlea; Hiatt, Susan M; Cooper, Gregory M; Aldinger, Kimberly A; Dobyns, William B; Mirzaa, Ghayda; Pierson, Tyler Mark; Baas, Frank; Chelly, Jamel; Cowan, Nicholas J; Keays, David Anthony. - In: NEURON. - ISSN 0896-6273. - (2018). [10.1016/j.neuron.2018.10.044]
Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations
DE LISE, STEFANO;Terrone, Gaetano;Del Giudice, Ennio;Brunetti-Pierri, Nicola;
2018
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
