Abstract

Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex1,2 but is also suggested to localize to the nuclear matrix and regulate chromatin structure3. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.

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Acknowledgements

We thank the individuals and their families reported herein for their participation in this research. We thank M. van Lohuizen (Netherlands Cancer Institute) for providing the Bmi1-knockout mice, A. Wagers for help with breeding the Bmi1-knockout mice and P. Baas for sharing human DNA samples. This research was supported by grants from the US National Institute of Neurological Disorders and Stroke (NINDS; R01NS035129) and the Fogarty International Center (R21TW008223) to C.A.W., the Dubai Harvard Foundation for Medical Research, the Simons Foundation and the Manton Center for Orphan Disease Research. G.H.M. was supported by the Young Investigator Award of the National Alliance for Research on Schizophrenia and Depression (NARSAD) as a NARSAD Lieber Investigator. V.S.G. is supported by the Medical Scientist Training Program of Harvard Medical School, with financial support from the US National institute of General Medical Sciences (NIGMS). C.A.W. and L.I.Z. are investigators of the Howard Hughes Medical Institute. Microscopy and image analyses were performed with support from the Cellular Imaging Core of the Boston Children's Hospital Intellectual and Developmental Disabilities Research Center.

Author information

Author notes

    • Ganeshwaran H Mochida
    •  & Vijay S Ganesh

    These authors contributed equally to the work.

Affiliations

  1. Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Ganeshwaran H Mochida
    • , Vijay S Ganesh
    • , Kutay D Atabay
    • , R Sean Hill
    • , Jillian M Felie
    • , Daniel Rakiec
    • , Danielle Gleason
    • , Brenda J Barry
    • , Jennifer N Partlow
    • , Wen-Hann Tan
    •  & Christopher A Walsh
  2. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Ganeshwaran H Mochida
    • , Vijay S Ganesh
    • , Kutay D Atabay
    • , R Sean Hill
    • , Jillian M Felie
    • , Daniel Rakiec
    • , Danielle Gleason
    • , Brenda J Barry
    • , Jennifer N Partlow
    •  & Christopher A Walsh
  3. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Ganeshwaran H Mochida
    • , Vijay S Ganesh
    • , Kutay D Atabay
    • , Katie L Kathrein
    • , Hsuan-Ting Huang
    • , R Sean Hill
    • , Jillian M Felie
    • , Daniel Rakiec
    • , Danielle Gleason
    • , Brenda J Barry
    • , Jennifer N Partlow
    • , Leonard I Zon
    •  & Christopher A Walsh
  4. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Ganeshwaran H Mochida
    • , Wen-Hann Tan
    • , Laurie J Glader
    • , Leonard I Zon
    •  & Christopher A Walsh
  5. Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Ganeshwaran H Mochida
  6. Harvard–Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, Massachusetts, USA.

    • Vijay S Ganesh
    •  & Athar N Malik
  7. Department of Morphologic Sciences, Cayetano Heredia University, Lima, Peru.

    • Maria I de Michelena
  8. Institute for Child Development–ARIE, Lima, Peru.

    • Hugo Dias
  9. Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Katie L Kathrein
    • , Hsuan-Ting Huang
    •  & Leonard I Zon
  10. Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Katie L Kathrein
    • , Hsuan-Ting Huang
    •  & Leonard I Zon
  11. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Katie L Kathrein
    • , Hsuan-Ting Huang
    •  & Leonard I Zon
  12. Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Anthony D Hill
  13. Complex Care Service, Division of General Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Laurie J Glader
  14. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

    • A James Barkovich
  15. Center for Integrative Brain Research, University of Washington, Seattle, Washington, USA.

    • William B Dobyns
  16. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.

    • Leonard I Zon
  17. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher A Walsh

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Contributions

G.H.M. designed the study, interpreted clinical information and brain MRIs, identified the disease locus, helped sequence candidate genes, analyzed the sequencing data to identify CHMP1A mutations, helped analyze the functional data and wrote the manuscript. V.S.G. performed RT-PCR, protein blots, mouse histology and immunohistochemistry, qPCR, ChIP and zebrafish morpholino experiments and wrote the manuscript. M.I.d.M. and H.D. ascertained family 1 and provided clinical information. K.D.A. performed zebrafish protein blots and mouse immunohistochemistry. K.L.K. performed the morpholino injections. H.-T.H. and L.I.Z. assisted with the morpholino experiments. R.S.H. helped organize genetic data and calculate LOD scores. J.M.F. and D.G. organized human samples and helped perform sequencing experiments. D.R. organized human samples and helped perform microsatellite analysis. A.D.H. assisted in immunohistochemical studies and imaging. A.N.M. assisted in ChIP. B.J.B. and J.N.P. organized clinical information and human samples. W.-H.T. and L.J.G. provided clinical information for family 3. A.J.B. interpreted the brain MRIs of the affected individuals. W.B.D. ascertained family 2 and provided clinical information. C.A.W. directed the overall research and wrote the manuscript.

Competing interests

L.I.Z. is a founder and stockholder of Fate Therapeutics, Inc., and a scientific advisor for Stemgent.

Corresponding author

Correspondence to Christopher A Walsh.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Note

Videos

  1. 1.

    Supplementary Video 1

    Brain MRI of CH2402. T1-weighted sagittal sequence reveals a very small cerebellum (vermis and hemispheres) and pons. There is no malformation of the cerebral cortex but the cerebral white matter volume is severely reduced with a fully formed but thin corpus callosum.

  2. 2.

    Supplementary Video 2

    Brain MRI of CH3102. T1-weighted saggital sequence shows a very small cerebellum (vermis and hemispheres), and pons. There is no malformation of the cerebral cortex but the cerebral white matter is moderately diminished in volume with a fully formed but thin corpus callosum.

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DOI

https://doi.org/10.1038/ng.2425