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首页> 外文期刊>Neuron >Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations
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Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

机译：Mast1中的突变引起巨型肠道癌症综合征，具有小脑发育不全和皮质畸形

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摘要

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-CHCM) 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.
机译：胼callosum畸形与广泛的神经发育疾病有关。我们报告说，在没有Mugalienc患病的情况下，MAST1中的Novo突变导致大脑癌症和皮质畸形（MCC-CHCM）引起巨型胼um综合征。我们表明MAST1是一种微管相关蛋白，其主要在后临床后神经元中表达，并且存在于树突和轴突隔室中。我们进一步表明，乳腺素1含有表型正常，而单个氨基酸（L278DEL）的缺失会概括患者中观察到的不同神经表型。在涉及Mast1微缺失的动物中，我们发现PI3K / AKT3 / MTOR途径不受干扰，而MAST2和MAST3水平降低，指示优势 - 负作用模式。最后，我们报告说，在患有自闭症和微头的患者中存在De Novo Mast1取代，提高了该基因突变的前景产生了一种神经发育疾病的谱。

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  • 来源
    《Neuron》 |2018年第6期|共20页
  • 作者

    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; Lise Stefano; Taylor Jenny C.; Terrone Gaetano; Vitiello Giuseppina; Del Giudice Ennio; Brunetti-Pierri Nicola; DAmico Alessandra; Reymond Alexandre; Voisin Norine; Bernstein Jonathan A.; Farrelly Ellyn; Kini Usha; Leonard Thomas A.; Valence Stephanie; 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;

  • 作者单位

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Leiden Univ Med Ctr Dept Clin Genet NL-2333 AA Leiden Netherlands;

    Vrije Univ Amsterdam Amsterdam UMC Clin Genet De Boelelaan 1117 Amsterdam Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Univ Calif San Diego Howard Hughes Med Inst Dept Neurosci La Jolla CA 92093 USA;

    NYU Langone Med Ctr Dept Biochem &

    Mol Pharmacol 550 1St Ave New York NY 10016 USA;

    Univ Paris 05 Hop Cochin Inst Cochin F-75014 Paris France;

    Univ Rochester Med Ctr Dept Neurol 601 Elmwood Ave Rochester NY 14642 USA;

    NIHR Oxford Biomed Res Ctr Oxford England;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

    NIHR Oxford Biomed Res Ctr Oxford England;

    NIHR Oxford Biomed Res Ctr Oxford England;

    Univ Naples Federico II Sect Pediat Dept Translat Med Sci I-80131 Naples Italy;

    Univ Naples Federico II Sect Pediat Dept Translat Med Sci I-80131 Naples Italy;

    Univ Naples Federico II Sect Pediat Dept Translat Med Sci I-80131 Naples Italy;

    Univ Naples Federico II Sect Pediat Dept Translat Med Sci I-80131 Naples Italy;

    Univ Naples Federico II Dept Adv Med Sci I-80131 Naples Italy;

    Univ Lausanne Ctr Integrat Genom CH-1015 Lausanne Switzerland;

    Univ Lausanne Ctr Integrat Genom CH-1015 Lausanne Switzerland;

    Stanford Sch Med Stanford CA 94305 USA;

    Stanford Childrens Hlth Palo Alto CA 94304 USA;

    Churchill Hosp Oxford Reg Genet Serv Dept Clin Genet Oxford OX3 7LJ England;

    Med Univ Vienna Max F Perutz Labs Vienna Bioctr VBC Ctr Med Biochem Campus Vienna Bioctr 5 A;

    Hop Trousseau AP HP Ctr Reference Malformat &

    Malad Congenitales Cerv F-75012 Paris France;

    Hop Trousseau AP HP Ctr Reference Malformat &

    Malad Congenitales Cerv F-75012 Paris France;

    Univ British Columbia BCWH Prov Med Genet Programme Vancouver BC V6H 3N1 Canada;

    HudsonAlpha Inst Biotechnol Huntsville AL 35806 USA;

    HudsonAlpha Inst Biotechnol Huntsville AL 35806 USA;

    Seattle Childrens Res Inst Ctr Integrat Brain Res Seattle WA 98101 USA;

    Seattle Childrens Res Inst Ctr Integrat Brain Res Seattle WA 98101 USA;

    Seattle Childrens Res Inst Ctr Integrat Brain Res Seattle WA 98101 USA;

    Inst Cedars Sinai Med Ctr Board Governors Regenerat Med Dept Pediat Los Angeles CA 90048 USA;

    Leiden Univ Med Ctr Dept Clin Genet NL-2333 AA Leiden Netherlands;

    Hop Univ Strasbourg Hop Civil Strasbourg Serv Diagnost Genet F-67091 Strasbourg France;

    NYU Langone Med Ctr Dept Biochem &

    Mol Pharmacol 550 1St Ave New York NY 10016 USA;

    Vienna Bioctr VBC Res Inst Mol Pathol Campus Vienna Bioctr 1 A-1030 Vienna Austria;

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