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

Details

Serval ID
serval:BIB_769F69929167
Type
Article: article from journal or magazin.
Collection
Publications
Title
Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations.
Journal
Neuron
Author(s)
Tripathy R., Leca I., van Dijk T., Weiss J., van Bon B.W., Sergaki M.C., Gstrein T., Breuss M., Tian G., Bahi-Buisson N., Paciorkowski A.R., Pagnamenta A.T., Wenninger-Weinzierl A., Martinez-Reza M.F., Landler L., Lise S., Taylor J.C., Terrone G., Vitiello G., Del Giudice E., Brunetti-Pierri N., D'Amico A., Reymond A., Voisin N., Bernstein J.A., Farrelly E., Kini U., Leonard T.A., Valence S., Burglen L., Armstrong L., Hiatt S.M., Cooper G.M., Aldinger K.A., Dobyns W.B., Mirzaa G., Pierson T.M., Baas F., Chelly J., Cowan N.J., Keays D.A.
ISSN
1097-4199 (Electronic)
ISSN-L
0896-6273
Publication state
Published
Issued date
19/12/2018
Peer-reviewed
Oui
Volume
100
Number
6
Pages
1354-1368.e5
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Agenesis of Corpus Callosum/complications, Agenesis of Corpus Callosum/diagnostic imaging, Agenesis of Corpus Callosum/genetics, Agenesis of Corpus Callosum/pathology, Animals, Animals, Newborn, Apoptosis/genetics, Brain/metabolism, Brain/pathology, Cells, Cultured, Cerebellum/abnormalities, Cerebellum/diagnostic imaging, Child, Developmental Disabilities/complications, Developmental Disabilities/diagnostic imaging, Developmental Disabilities/genetics, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental/genetics, Humans, Male, Malformations of Cortical Development/complications, Malformations of Cortical Development/diagnostic imaging, Malformations of Cortical Development/genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins/deficiency, Microtubule-Associated Proteins/genetics, Mutation/genetics, Nerve Tissue Proteins/metabolism, Nervous System Malformations/complications, Nervous System Malformations/diagnostic imaging, Nervous System Malformations/genetics, PAX6 Transcription Factor/metabolism, MAST1, cerebellar hypoplasia, corpus callosum, microdeletion, microtubules
Pubmed
Web of science
Create date
26/11/2018 14:53
Last modification date
20/08/2019 15:33
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