The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal–lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15–Vps34 complex and the Nischarin–Pak1 signaling hub in the development of the telencephalon.

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We thank the family for the donation of the genetic and biological material. We also acknowledge the input of P. Potter and S. Wells from the mutagenesis program at MRC Harwell and the MRC funding that underpinned it (MC U142684172). We are indebted to R. Williams for modeling the VPS15 human mutation. We also thank the transgenic, bio-optics, proteomic and graphics services groups at the IMP/IMBA. We thank The National Center for Medical Genomics (LM2015091) for providing allelic frequencies in ethnically matched populations (project CZ.02.1.01/0.0/0.0/16_013/0001634). We thank Boehringer Ingelheim and the FWF for funding this research (D.A.K., I914, P24267). The human studies were funded by the European Community’s 7th Framework Program (FP7/2007-2013). S.K., A.P. and V.S. were supported by institutional programs of Charles University in Prague (UNCE 204011, PROGRES-Q26/LF1 and SVV 260367/2017). We acknowledge grants 15-28208A and RVO-VFN 64165 from the Ministry of Health of the Czech Republic and the project LQ1604 NPU II from the Ministry of Education.

Author information


  1. Institute of Molecular Pathology (IMP), Vienna Biocentre (VBC), Vienna, Austria

    • Thomas Gstrein
    • , Ines Leca
    • , Martin Breuss
    • , Sandra Pilat-Carotta
    • , Andi H. Hansen
    • , Ratna Tripathy
    • , Anna K. Traunbauer
    • , Tobias Hochstoeger
    • , Gavril Rosoklija
    • , Lukas Landler
    • , Gerhard Dürnberger
    • , Johannes Zuber
    • , Karl Mechtler
    •  & David A. Keays
  2. Wellcome Trust Center for Human Genetics (WTCHG), Oxford, UK

    • Andrew Edwards
    •  & Jonathan Flint
  3. Institute of Inherited Metabolic Disorders, Charles University, Prague, Czech Republic

    • Anna Přistoupilová
    • , Viktor Stránecký
    •  & Stanislav Kmoch
  4. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

    • Anna Přistoupilová
    • , Marta Gut
    • , Sergi Beltran
    •  & Ivo Gut
  5. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    • Anna Přistoupilová
    • , Marta Gut
    • , Sergi Beltran
    •  & Ivo Gut
  6. Institute for Molecular Biotechnology (IMBA), Vienna, Austria

    • Marco Repic
  7. Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK

    • Thomas M. Keane
    •  & David J. Adams
  8. Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    • Tomas Honzik
  9. Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    • Elliott Sherr


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A.E., J.F. and D.A.K. performed the phenotypic screen and genetic mapping. T.M.K. and D.J.A. did the whole-exome sequencing on the Marble mouse. T.G., G.R. and T.Hochstoeger analyzed the expression of Vps15. T.G., I.L., M.B., S.P.-C., A.H.H., R.T. and L.L. were responsible for the characterization of the Marble and KO mouse lines. K.M. and G.D. undertook the mass spectroscopy experiments. M.R. and T.G. performed the in utero electroporation analysis. A.P., T.Honzik, M.G., S.B., E.S., S.K., V.S. and I.G. collated the clinical data and performed whole-exome sequencing and analysis of the L1224R patient. T.G. performed the functional experiments. A.K.T., T.G. and J.Z. designed and performed the lentiviral rescue experiment. T.G. and D.A.K. wrote the manuscript and all authors commented on it.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David A. Keays.

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