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Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

Authors

  • Ingrid E. Scheffer MB, BS, PhD,

    Corresponding author
    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
    2. Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
    3. Department of Paediatrics, University of Melbourne, Melbourne, Australia
    • Address correspondence to Dr Scheffer, Epilepsy Research Centre, Austin Health, 245 Burgundy St, Heidelberg, Victoria 3081, Australia. E-mail: scheffer@unimelb.edu.au or Dr Dibbens, Epilepsy Research Program, School of Pharmacy and Medical Sciences, P4-47, University of South Australia, Adelaide, South Australia 5000, Australia. E-mail: leanne.dibbens@unisa.edu.au

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  • Sarah E. Heron BSc, PhD,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    2. Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
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  • Brigid M. Regan BSc,

    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
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  • Simone Mandelstam MB, ChB,

    1. Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Australia
    3. Department of Radiology, University of Melbourne, Melbourne, Australia
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  • Douglas E. Crompton MBBS, PhD,

    1. Department of Neurology, Northern Health, Melbourne, Australia
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  • Bree L. Hodgson Dip Biomed Sci,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    2. Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
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  • Laura Licchetta MD,

    1. IRCCS, Institute of Neurological Science, University of Bologna, Bologna, Italy
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  • Federica Provini MD, PhD,

    1. IRCCS, Institute of Neurological Science, University of Bologna, Bologna, Italy
    2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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  • Francesca Bisulli MD, PhD,

    1. IRCCS, Institute of Neurological Science, University of Bologna, Bologna, Italy
    2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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  • Lata Vadlamudi MB, BS, PhD,

    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
    2. School of Medicine, University of Queensland and Department of Neurology, Brisbane, Australia
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  • Jozef Gecz PhD,

    1. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
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  • Alan Connelly PhD,

    1. Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
    2. Department of Medicine, Austin Health, University of Melbourne, Melbourne, Australia
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  • Paolo Tinuper MD,

    1. IRCCS, Institute of Neurological Science, University of Bologna, Bologna, Italy
    2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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  • Michael G. Ricos BSc, PhD,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    2. Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
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  • Samuel F. Berkovic MD, FRS,

    1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Melbourne, Australia
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  • Leanne M. Dibbens BSc, PhD

    Corresponding author
    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    2. Sansom Institute for Health Research, University of South Australia, Adelaide, Australia
    • Address correspondence to Dr Scheffer, Epilepsy Research Centre, Austin Health, 245 Burgundy St, Heidelberg, Victoria 3081, Australia. E-mail: scheffer@unimelb.edu.au or Dr Dibbens, Epilepsy Research Program, School of Pharmacy and Medical Sciences, P4-47, University of South Australia, Adelaide, South Australia 5000, Australia. E-mail: leanne.dibbens@unisa.edu.au

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Abstract

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787

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