Dataset Information

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

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.

SUBMITTER: Tripathy R

PROVIDER: S-EPMC6436622 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Tripathy Ratna R Leca Ines I van Dijk Tessa T Weiss Janneke J van Bon Bregje W BW Sergaki Maria Christina MC Gstrein Thomas T Breuss Martin M Tian Guoling G Bahi-Buisson Nadia N Paciorkowski Alexander R AR Pagnamenta Alistair T AT Wenninger-Weinzierl Andrea A Martinez-Reza Maria Fernanda MF Landler Lukas L Lise Stefano S Taylor Jenny C JC Terrone Gaetano G Vitiello Giuseppina G Del Giudice Ennio E Brunetti-Pierri Nicola N D'Amico Alessandra A Reymond Alexandre A Voisin Norine N Bernstein Jonathan A JA Farrelly Ellyn E Kini Usha U Leonard Thomas A TA Valence Stéphanie S Burglen Lydie L Armstrong Linlea L Hiatt Susan M SM Cooper Gregory M GM Aldinger Kimberly A KA Dobyns William B WB Mirzaa Ghayda G Pierson Tyler Mark TM Baas Frank F Chelly Jamel J Cowan Nicholas J NJ Keays David Anthony DA

Neuron 20181115 6

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 phenotypicall ...[more]

PMID: 30449657

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Project description:Agenesis of the corpus callosum (ACC), cerebellar hypoplasia (CBLH), and polymicrogyria (PMG) are severe congenital brain malformations with largely undiscovered causes. We conducted a large-scale chromosomal copy number variation (CNV) discovery effort in 255 ACC, 220 CBLH, and 147 PMG patients, and 2,349 controls. Compared to controls, significantly more ACC, but unexpectedly not CBLH or PMG patients, had rare genic CNVs over one megabase (p?=?1.48×10?³; odds ratio [OR]?=?3.19; 95% confidence interval [CI]?=?1.89-5.39). Rare genic CNVs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. Compared to controls, significantly more ACC but not CBLH or PMG patients had rare CNVs impacting over 20 genes (p?=?0.01; OR?=?2.95; 95% CI?=?1.69-5.18). Independent qPCR confirmation showed that 9.4% of ACC patients had de novo CNVs. These, in comparison to inherited CNVs, preferentially overlapped de novo CNVs previously observed in patients with autism spectrum disorders (p?=?3.06×10??; OR?=?7.55; 95% CI?=?2.40-23.72). Interestingly, numerous reports have shown a reduced corpus callosum area in autistic patients, and diminished social and executive function in many ACC patients. We also confirmed and refined previously known CNVs, including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current ACC cohort. We found six novel CNVs, each in a single patient, that are likely deleterious: deletions of 1p31.3-p31.1, 1q31.2-q31.3, 5q23.1, and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. One ACC patient with microcephaly had a paternally inherited deletion of 16p13.11 that included NDE1. Exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of NDE1, revealing the complexity of ACC genetics. This is the first systematic study of CNVs in congenital brain malformations, and shows a much higher prevalence of large gene-rich CNVs in ACC than in CBLH and PMG.

Dataset Information

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

Publications

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

Similar Datasets

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