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Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly–capillary malformation syndrome

Nature Genetics volume 45, pages 556–562 (2013)Cite this article

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Abstract

Microcephaly–capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor–mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome.

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Figure 1: Neuroimaging and clinical features of MIC-CAP syndrome in patient 9.1.
Figure 2: Mutations in STAMBP cause MIC-CAP syndrome.
Figure 3: Elevated amounts of ubiquitin protein aggregates, apoptosis and autophagic flux in MIC-CAP syndrome.
Figure 4: Elevated RAS-GTP (active RAS) and activated PI3 kinase in MIC-CAP syndrome.
Figure 5: Elevated and insensitive RAS-MAPK and PI3K-AKT-mTOR signaling in MIC-CAP syndrome.

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Acknowledgements

The authors would like to thank the study patients and their families, without whose participation this work would not be possible. This work was funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049) (to K.M.B.). Additional funding was provided by Genome Quebec and Genome British Columbia (to K.M.B.), the US National Institutes of Health under National Institute of Neurological Disorders and Stroke (NINDS) grant NS058721 (to W.B.D.), as well as National Institute of Child Health and Human Development (NICHD) grant HD36657 and National Institute of General Medicine Sciences (NIGMS) grant 5-T32-GM08243 (to J.M.G.) and the Leukaemia Lymphoma Research (UK), Medical Research Council (UK) and Cancer Research UK (CR-UK) (to M.O.). The authors acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, as well as M. Moellers, (Pediatric Radiology, Evangelisches Krankenhaus Bielefeld). This work was selected for study by the FORGE Canada Steering Committee, consisting of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (University of Montreal) and S. Scherer (University of Toronto). L.M.M. is supported by a Frederick Banting Graduate Scholarship from CIHR. M.O. is a CR-UK Senior Cancer Research Fellow. K.M.B. is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics.

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Author notes

  1. William B Dobyns, Mark O'Driscoll and Kym M Boycott: These authors jointly directed this work.

Authors and Affiliations

  1. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada

    Laura M McDonell, Chandree L Beaulieu, Janet Marcadier, Michael T Geraghty, Dennis E Bulman & Kym M Boycott

  2. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    Ghayda M Mirzaa & Soma Das

  3. Genome Damage and Stability Centre, University of Sussex, Brighton, UK

    Diana Alcantara & Mark O'Driscoll

  4. McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada

    Jeremy Schwartzentruber

  5. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

    Melissa T Carter

  6. Department of Electrical and Computer Engineering, Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada

    Leo J Lee & Brendan J Frey

  7. Department of Genetics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

    Carol L Clericuzio

  8. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

    John M Graham Jr

  9. Institute of Human Genetics, University Clinic Freiburg, Freiburg, Germany

    Deborah J Morris-Rosendahl

  10. Bethel Epilepsy Center, Krankenhaus Mara, Bielefeld, Germany

    Tilman Polster

  11. Department of Neurology, Connecticut Children's Medical Center, Hartford, Connecticut, USA

    Gyula Acsadi

  12. Genetics Service of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia

    Sharron Townshend

  13. Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia

    Simon Williams

  14. Department of Pediatric Rehabilitation, Princess Margaret Hospital, Perth, Western Australia, Australia

    Simon Williams

  15. Department of Pediatric Dermatology, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia

    Anne Halbert

  16. Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, Nantes, France

    Bertrand Isidor & Albert David

  17. Department of Neurology, Washington University, St. Louis, Missouri, USA

    Christopher D Smyser

  18. Department of Neurology, University of Washington and Seattle Children's Research Institute, Seattle, Washington, USA

    Alex R Paciorkowski

  19. Department of Pediatrics, Washington University, St. Louis, Missouri, USA

    Marcia Willing

  20. Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

    John Woulfe

  21. Department of Human Genetics, McGill University, Montréal, Quebec, Canada

    Jacek Majewski

  22. Department of Pediatrics, University of Washington, Seattle, Washington, USA

    William B Dobyns

  23. Department of Neurology, University of Washington, Seattle, Washington, USA

    William B Dobyns

  24. Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA

    William B Dobyns

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  1. Laura M McDonell
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Consortia

FORGE Canada Consortium

  • K Boycott
  • , J Friedman
  • , J Michaud
  • , F Bernier
  • , M Brudno
  • , B Fernandez
  • , B Knoppers
  • , M Samuels
  •  & S Scherer

Contributions

K.M.B., M.O., W.B.D. and D.E.B. directed the study. M.T.C., L.J.L., C.L.C., J.M.G., D.J.M.-R., T.P., G.A., S.T., S.W., A.H., B.I., A.D., C.D.S., A.R.P., M.W., J.W., S.D., M.T.G., G.M.M., W.B.D. and K.M.B. provided clinical data. L.M.M. performed Sanger sequencing, genotyping studies and variant analysis supervised by K.M.B. and D.E.B. D.A. performed the protein biochemistry and cell biology studies, which were directed by M.O. J.S. and J. Majewski performed exome variant calling analysis. The manuscript was written by L.M.M., G.M.M., M.O. and K.M.B. FORGE Canada Consortium provided the clinical and bioinformatic infrastructure under the direction of K.M.B. assisted by C.L.B. and J. Marcadier. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Mark O'Driscoll or Kym M Boycott.

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Competing interests

The authors declare no competing financial interests.

Additional information

Membership of the Steering Committee for the Consortium is provided in the Acknowledgments section.

Supplementary information

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Supplementary Figures 1–6 and Supplementary Tables 1–3 (PDF 854 kb)

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McDonell, L., Mirzaa, G., Alcantara, D. et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly–capillary malformation syndrome. Nat Genet 45, 556–562 (2013). https://doi.org/10.1038/ng.2602

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