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

Ratna Tripathy, Ines Leca, Tessa van Dijk, Janneke Weiss, Bregje W. van Bon, Maria Christina Sergaki, Thomas Gstrein, Martin Breuss, Guoling Tian, Nadia Bahi-Buisson, Alexander R. Paciorkowski, Alistair T. Pagnamenta, Andrea Wenninger-Weinzierl, Maria Fernanda Martinez-Reza, Lukas Landler, Stefano Lise, Jenny C. Taylor, Gaetano Terrone, Giuseppina Vitiello, Ennio Del GiudiceNicola Brunetti-Pierri, Alessandra D'Amico, Alexandre Reymond, Norine Voisin, Jonathan A. Bernstein, Ellyn Farrelly, Usha Kini, Thomas A. Leonard, Stéphanie Valence, Lydie Burglen, Linlea Armstrong, Susan M. Hiatt, Gregory M. Cooper, Kimberly A. Aldinger, William B. Dobyns, Ghayda Mirzaa, Tyler Mark Pierson, Frank Baas, Jamel Chelly, Nicholas J. Cowan, David Anthony Keays

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1354-1368.e5
Issue number6
StatePublished - Dec 19 2018
Externally publishedYes

Bibliographical note

Funding Information:
D.A.K. wishes to thank the Austrian Science Foundation ( FWF , P21092 and I2681-B27 ). We wish to acknowledge the support of Boehringer Ingelheim , who fund basic science at the IMP. We wish to thank the CAUSES study, specifically Shelin Adam, Christele Du Souich, Jane Gillis, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman. We would also thank Prof. Dr. Bwee Tien Poll and Dr. Saskia Maas for including patient P4 in the study and providing clinical information. T.M.P. is supported by the Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. G.M. is generously supported by the National Institute of Neurological Disorders and Stroke ( NINDS ) ( K08NS092898 ) and Jordan’s Guardian Angels . We are indebted to Dr. Vissers for her help with patient P8. J.C.T. and A.T.P. are funded by Oxford NIHR Biomedical Research Centre . N.J.C. acknowledges the support of the NIH ( R01GM097376 ). This work was supported by grants from the Swiss National Science Foundation ( 31003A , 182632 ) to A.R. G.M.C. and S.M.H. are grateful for support from the National Human Genome Research Institute ( UM1HG007301 ). T.A.L. is funded by the Austrian Science Fund (FWF P28135 ), and W.B.D. is supported by NIH ( 1R01NS058721 ).


  • MAST1
  • cerebellar hypoplasia
  • corpus callosum
  • microdeletion
  • microtubules

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