Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome Corpus callosum malformations are associated

Article

Mutations in MAST1 Caus

Graphical Abstract

Highlights

d Mast1 associates with the microtubule cytoskeleton in a

MAP-dependent manner

d Mast1 is expressed in postmitotic neurons but not neuronal

progenitors

d Mast1 Leu278delmice have an enlarged corpus callosum and

smaller cerebellum

d More axons cross the midline in Mast1 Leu278del mice

despite cortical apoptosis

Tripathy et al., 2018, Neuron 100, 1–15 December 19, 2018 ª 2018 Elsevier Inc. https://doi.org/10.1016/j.neuron.2018.10.044

Authors

Ratna Tripathy, Ines Leca,

Tessa van Dijk, ..., Jamel Chelly,

Nicholas J. Cowan,

David Anthony Keays

Correspondence keays@imp.ac.at

In Brief

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.

mailto:keays@imp.ac.�at https://doi.org/10.1016/j.neuron.2018.10.044

Please cite this article in press as: Tripathy et al., Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations, Neuron (2018), https://doi.org/10.1016/j.neuron.2018.10.044

Neuron

Article

Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations Ratna Tripathy,1 Ines Leca,1 Tessa van Dijk,2 Janneke Weiss,3 Bregje W. van Bon,4 Maria Christina Sergaki,1

Thomas Gstrein,1 Martin Breuss,5 Guoling Tian,6 Nadia Bahi-Buisson,7 Alexander R. Paciorkowski,8

Alistair T. Pagnamenta,9 Andrea Wenninger-Weinzierl,1 Maria Fernanda Martinez-Reza,1 Lukas Landler,1 Stefano Lise,9

Jenny C. Taylor,9 Gaetano Terrone,10 Giuseppina Vitiello,10 Ennio Del Giudice,10 Nicola Brunetti-Pierri,10,12

Alessandra D’Amico,11 Alexandre Reymond,13 Norine Voisin,13 Jonathan A. Bernstein,14 Ellyn Farrelly,15 Usha Kini,16

Thomas A. Leonard,17 Stéphanie Valence,18 Lydie Burglen,18 Linlea Armstrong,19 Susan M. Hiatt,20 Gregory M. Cooper,20

Kimberly A. Aldinger,21 William B. Dobyns,21 Ghayda Mirzaa,21 Tyler Mark Pierson,22 Frank Baas,2 Jamel Chelly,23

Nicholas J. Cowan,6 and David Anthony Keays1,24,* 1Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, Vienna Biocenter (VBC), Vienna 1030, Austria 2Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands 3Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands 4Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands 5Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA 6Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA 7Université Paris Descartes, Institut Cochin Hôpital Cochin, 75014 Paris, France 8Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA 9NIHR Oxford Biomedical Research Centre, Oxford, UK, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK 10Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, 80131 Naples, Italy 11Department of Advanced Medical Sciences, University of Naples Federico II, 80131 Naples, Italy 12Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Naples, Italy 13Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland 14Stanford School of Medicine, Stanford, CA 94305, USA 15Stanford Children’s Health, Palo Alto, CA 94304, USA 16Department of Clinical Genetics, Oxford Regional Genetics Service, Churchill Hospital, Oxford OX3 7LJ, UK 17Center for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Vienna Biocenter (VBC), Campus Vienna

Biocenter 5, 1030 Vienna, Austria 18Centre de référence des Malformations et Maladies Congénitales du Cervelet et Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, 75012 Paris, France 19Provincial Medical Genetics Programme, BCWH and Department of Medical Genetics, University of British Columbia, Vancouver,

BC V6H 3N1, Canada 20HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA 21Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA 98101, USA 22Departments of Pediatrics and Neurology & the Board of Governors Regenerative Medicine, Institute Cedars Sinai Medical Center,

Los Angeles, CA 90048, USA 23Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France 24Lead Contact

*Correspondence: keays@imp.ac.at

https://doi.org/10.1016/j.neuron.2018.10.044

SUMMARY

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 neu- rons and is present in both dendritic and axonal com- partments. 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 pa- tients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unper- turbed, whereas Mast2 and Mast3 levels are dimin- ished, indicative of a dominant-negative mode of action. Finally, we report that de novoMAST1 substi- tutions are present in patients with autism andmicro- cephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Neuron 100, 1–15, December 19, 2018 ª 2018 Elsevier Inc. 1

mailto:keays@imp.ac.at https://doi.org/10.1016/j.neuron.2018.10.044

MAST1 gene

MAST1 protein p. L ys

27 6d

el

p. Le

u2 78

de l

1 61 335 373 652 968 1050 1570

p. Gl

u1 94

de l

p. Gl

y5 17

Se r

DUF1908 Kinase PDZ

c. 82

5_ 82

7d el

c. 83

1_ 83

3d el

c. 15

49 G>

A

c. 58

0_ 58

2d el

V

W

Y

X

Z

****

Pelleted mMast1

w/ M

AP s

w/ o M

AP s

Pelleted mMast1

TnT mMast1

K2 76

de l

L2 78

de l

E1 94

de l

G5 19

S WT

WT

E1 94

de l

K2 76

de l

L2 78

de l

G5 19

S 0.0

0.5

1.0

1.5

2.0

2.5 P

el le

te d

M as

t1 /T

nT *

U

P V

P1: Glu194 del

P2: Lys276 del

P3: Leu278 del

P5: Gly517Ser

P6: Gly517Ser

P4: Gly517Ser

A B C D

E F G H

I K L

M O

N

J

N P

Q R S T

w/ MAPs w/o MAPs 0.0

0.2

0.4

0.6

0.8

P el

le te

d M

as t1

/T nt

Tn T I

np ut

Figure 1. Patients with MAST1 Mutations

(A–T) Selected magnetic resonance images from patients P1 (A–D), P2 (E–H), P3 (I and J), P4 (K and L), P5 (M–P), and P6 (Q–T) in the midline sagittal plane (A, E, I,

K, M), parasagittal plane (Q), and axial planes through the brainstem (F and N), lateral ventricles (B, C, G, J, L, O, R, S, and T), and high convexities (D, H, and P). All

patients have a cortical malformation or dysgyria characterized by diffuse undersulcation, shallow sulci (arrowheads in B, C, G, J, L, O, R, S, and T point to

selectedmore obvious areas), and, in themore severely affected, mildly thick cortex (G and J; thus consistent with mild lissencephaly). While diffused, the cortical

malformation appears most severe in the posterior frontal and perisylvian regions. The lateral ventricles are mildly to moderately enlarged, and the corpus

callosum is abnormally thick (arrows in A, E, I, K, M, and Q), accompanied by mildly thick white matter. The brainstem, especially the pons, is mildly (E) or

moderately (A, I, K, M, and Q) small, and in at least one child a prominent ventral midline cleft of the pons is seen (arrow in N). Available axial images through the

high convexity of the cerebral hemispheres showed very dysplastic, longitudinally oriented gyral pattern (long arrows in D, H, and P).

(legend continued on next page)

2 Neuron 100, 1–15, December 19, 2018

Please cite this article in press as: Tripathy et al., Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations, Neuron (2018), https://doi.org/10.1016/j.neuron.2018.10.044

Please cite this article in press as: Tripathy et al., Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations, Neuron (2018), https://doi.org/10.1016/j.neuron.2018.10.044

INTRODUCTION

The bilateral integration of sensory, motor, and cognitive inputs

is mediat