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CHMP1A Encodes an Essential Regulator of BMI1-INK4A in Cerebellar Development

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CHMP1A Encodes an Essential Regulator of BMI1-INK4A in Cerebellar Development CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Mochida, Ganeshwaran H., Vijay S. Ganesh, Maria I. de Michelena, Hugo Dias, Kutay D. Atabay, Katie L. Kathrein, Emily Huang, et al. 2013. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nature genetics 44(11): 1260-1264. Published Version doi:10.1038/ng.2425 Accessed February 19, 2015 12:08:00 PM EST Citable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11181050 Terms of Use This article was downloaded from Harvard University's DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA (Article begins on next page) NIH Public Access Author Manuscript Nat Genet. Author manuscript; available in PMC 2013 May 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nat Genet. 2012 November ; 44(11): 1260–1264. doi:10.1038/ng.2425. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development Ganeshwaran H. Mochida1,2,3,4,5,*, Vijay S. Ganesh1,2,3,6,*, Maria I. de Michelena7, Hugo Dias8, Kutay D. Atabay1,2,3, Katie L. Kathrein3,9,10,11, Emily Huang3,9,10,11, R. Sean Hill1,2,3, Jillian M. Felie1,2,3, Daniel Rakiec1,2,3, Danielle Gleason1,2,3, Anthony D. Hill12, Athar N. Malik6, Brenda J. Barry1,2,3, Jennifer N. Partlow1,2,3, Wen-Hann Tan1,4, Laurie J. Glader4,13, A. James Barkovich14, William B. Dobyns15, Leonard I. Zon3,4,9,10,11, and Christopher A. Walsh1,2,3,4,16 1Division of Genetics, Department of Medicine, Boston Children’s Hospital, Boston, MA, USA 2Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA 3Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA 4Departments of Pediatrics, Harvard Medical School, Boston, MA, USA 5Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 6Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA Corresponding author: Dr. Christopher A. Walsh, Division of Genetics, Boston Children’s Hospital, 300 Longwood Ave, CLS 15062.2, Boston, MA 02115, [email protected], Phone: 617-919-2923, Fax: 617-919-2010. *These authors contributed equally to the work. URLs UCSC Human Genome Browser: http://genome.ucsc.edu/ Primer3: http://frodo.wi.mit.edu/primer3/ NetGene2: http://www.cbs.dtu.dk/services/NetGene2/ dbSNP: http://www.ncbi.nlm.nih.gov/projects/SNP/ 1000 Genomes Project: http://www.1000genomes.org/ NHLBI Exome Sequencing Project: http://evs.gs.washington.edu/EVS/ Accession codes Human CHMP1A: NM_002768 Human CDKN2A: NM_000077 (INK4A), NM_058195 (ARF) Zebrafish chmp1a: NM_200563 Zebrafish bmi1a: NM_194366 Zebrafish bmi1b: NM_001080751 Zebrafish cdkn2a: XM_002660468 Mouse Chmp1a: NM_145606 Author contributions G.H.M. designed the study, interpreted clinical information and brain MRI, 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, western blot, mouse histology and immunohistochemistry, quantitative PCR, chromatin immunoprecipitation, zebrafish morpholino experiments, and wrote the manuscript. M.I.M. and H.D. ascertained Family 1 and provided clinical information. K.D.A. performed zebrafish western blot and mouse immunohistochemistry. K.L.K. performed the morpholino injections. E.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 immunohistochemical studies and imaging. A.N.M. assisted with the chromatin immunoprecipitation. B.J.B. and J.N.P. organized clinical information and human samples. W.H.T. and L.J.G. provided clinical information of Family 3. A.J.B. interpreted brain MRI 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 financial interests The authors declare no competing financial interests. Mochida et al. Page 2 7Department of Morphologic Sciences, Cayetano Heredia University, Lima, Perú 8Institute for Child Development, ARIE, Lima, Perú NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 9Stem Cell Program, Boston Children’s Hospital, Boston, MA, USA 10Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA 11Dana-Farber Cancer Institute, Boston, MA, USA 12Department of Neurology, Boston Children’s Hospital, Boston, MA, USA 13Complex Care Outpatient Program, Division of General Pediatrics, Boston Children’s Hospital, Boston, MA, USA 14Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA 15Center for Integrative Brain Research, University of Washington, Seattle, WA, USA 16Department of Neurology, Harvard Medical School, Boston, MA, USA Charged multivesicular body protein 1A/Chromatin modifying protein 1A (CHMP1A) 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 to 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, and chromatin immunoprecipitation suggests a 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 orthologue 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 CNS progenitor cells. As part of ongoing studies of human disorders of neural progenitor proliferation, we identified three families characterized by underdevelopment of the cerebellum, pons, and cerebral cortex (Fig. 1a–d). In a consanguineous pedigree of Peruvian origin, three children in two branches were affected (Fig. 1e; Family 1). Two additional pedigrees from Puerto Rico showed similar pontocerebellar hypoplasia and microcephaly (Fig. 1e; Family 2 and 3). Brain MRI of affected individuals from all families show severe reduction of the cerebellar vermis and hemispheres. Strikingly, the cerebellar folds (“folia”) are relatively preserved despite the extremely small cerebellar size (Fig. 1a–d, Supplementary Videos 1, 2). All affected individuals had severe pontocerebellar hypoplasia, though affected individuals in Family 1 showed better motor and cognitive function than those in Family 2 and 3 (Supplementary Note, Clinical Information). Genome-wide linkage analysis of Family 1 and 2 using single nucleotide polymorphism (SNP) microarrays implicated only one region on chromosome 16q as linked and homozygous in all six affected individuals (Fig. 1e, Supplementary Fig. 1), with a maximum multipoint LOD score of 3.68 (Fig. 1e). Although Families 2 and 3 are not highly informative for linkage analysis, their shared homozygosity provides additional support for this locus. Furthermore, Families 2 and 3 shared the same haplotype (Supplementary Fig. 1), suggesting a founder effect. Sequencing of 42 genes within the candidate interval on 16q24.3 revealed homozygous variants predicted to be deleterious in the CHMP1A gene Nat Genet. Author manuscript; available in PMC 2013 May 01. Mochida et al. Page 3 only. CHMP1A consists of seven exons encoding a 196 amino acid protein (Supplementary Note, CHMP1A isoforms). Affected individuals in Family 2 and 3 had a homozygous NIH-PA Author Manuscript NIH-PA Author Manuscriptnonsense NIH-PA Author Manuscript variant in exon 3, predicted to prematurely terminate translation (c.88C>T; Q30X; Fig. 2a). Family 1 showed a homozygous variant in intron 2 of CHMP1A (c.28-13G>A; Fig. 2a) predicted to create an aberrant splice acceptor site leading to an 11 base pair insertion into the spliced mRNA product (Supplementary Fig. 2a). The two mutations were absent from dbSNP, 281 neurologically normal European control DNA samples (562 chromosomes), the 1000 Genomes Project database4, and approximately 5000 control exomes from the NHLBI Exome Sequencing Project. We sequenced CHMP1A in 64 individuals with other cerebellar anomalies without finding additional mutations, but none of these patients shared the rare and distinctive pattern of hypoplasia seen in the individuals with CHMP1A mutations. RT-PCR analysis of CHMP1A in lymphoblastoid cells from affected individuals from Family 1 (CH3101 and CH3105) identified the predicted aberrant transcript with the 11 base pair insertion and a second aberrant transcript with a 21 base pair insertion, but no normal CHMP1A transcript (Supplementary Fig. 2b). In the parents of affected children from Family 1, and in unaffected control
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