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CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development


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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Figure 1: Brain MRI and linkage mapping of pontocerebellar hypoplasia with microcephaly.
Figure 2: Loss-of-function mutations in CHMP1A and dysregulation of INK4A in cell lines from affected individuals.
Figure 3: Genetic links between CHMP1A and BMI1 in zebrafish and mice.
Figure 4: CHMP1A and BMI1 expression in cultured cells and the developing mouse brain.

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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.

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Authors and Affiliations



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.

Corresponding author

Correspondence to Christopher A Walsh.

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Competing interests

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Note (PDF 4341 kb)

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. (MOV 907 kb)

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. (MOV 1752 kb)

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Mochida, G., Ganesh, V., de Michelena, M. et al. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet 44, 1260–1264 (2012).

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