Abstract
The exon-junction complex (EJC) performs essential RNA processing tasks1,2,3,4,5. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR)6, caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10−228) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR7, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
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Acknowledgements
We thank C. Langford and P. Ellis for performing the enrichment for the exome sequencing, S. Balasubramaniam for assistance with data processing and the Wellcome Trust Sanger Institute sequencing core for sequencing. We thank V. Mooser from GlaxoSmithKline, G. Waeber and P. Vollenweider from CoLaus and J. Durham, C. Scott and colleagues at the Sanger Institute for providing access to their collection of whole-exome sequencing data for the CoLaus cohort12. We thank R. Durbin, B. Göttgens and I. Palacios for comments on the manuscript. This study makes use of data generated by the UK10K Consortium, which were derived from samples from the TwinsUK cohort. A full list of the investigators who contributed to the generation of the data is available from their website (see URLs). The study was supported by grants from the National Institutes for Health Research (NIHR; RP-PG-0310-1002 to C.G., G.K., P.A.S. and W.H.O.), the British Heart Foundation (FS/09/039 to C.G. and RG/09/12/28096 to C.A.A.), project grants from the Wellcome Trust (WT-082597/Z/07/Z to A.C. and WT-084183/2/07/2 to J.C.S.), grants by the Deutsche Forschungsgemeinschaft (SCHU1421/3-1 to H.S.) and the Sanitätsrat Dr. Emil Alexander Hübner-und-Gemahlin-Stiftung (T114/17644/2008/sm to H.S.), by the Excellentie Financiering KULeuven (EF/05/013), by research grants from the Fonds Wetenschappelijk Onderzoek-Vlaanderen (G.0490.10N and G.0743.09) and by a grant from the Research Council of the University of Leuven (Onderzoeksraad–K.U. Leuven; GOA/2009/13 to C.T., K.F. and C.v.G.). The project made use of NHS Blood and Transplant donors from the Cambridge BioResource (see URLs). This local resource for genotype-phenotype association studies is supported by a grant from the NIHR to the Cambridge Biomedical Research Centre (RBAG096 to J.C.S. and J.D.J.). D.S.P. and M.K. were supported by a Marie-Curie NetSim Initial Training Network grant (EC-215820). The French cases were collected with support from the Gis-Maladies Rares, Diagnostic Différentiel des Purpuras Thrombopéniques Idiopathiques Chroniques et des Thrombopénies Congénitales (DIATROC) program and INSERM (ANR-08-GENO-028-03). Funding for UK10K was provided by the Wellcome Trust (WT091310).
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C.A.A. performed next-generation sequence, Sanger sequence, genetic and statistical analyses. D.S.P. performed EMSA experiments, FAIRE-seq experiments and analysis, and in silico transcription factor binding analysis under the supervision of P.D. H.S., K.F., J.F., K.S., C.T. and R.N.-E. ascertained deletion status for TAR cases. K.F. and C.T. performed luciferase assays. H.S., K.F., C.T., C.G. and C.M.H. performed protein blot experiments. J.C.S. performed the Sanger sequencing and analyzed the data. P.A.S. performed quantitative PCR (qPCR) and allele-specific expression experiments. J.D.J. performed allele-specific expression experiments. A.C. performed the zebrafish knockdown study with input from D.L.S. M.K. analyzed the megakaryocyte RNA sequencing (RNA-seq) data under the supervision of P.B. G.K. supervised exome sequencing. J.G.S. supervised the Cambridge BioResource study. N.H. and M.E.H. performed the CNV analyses. H.S., M.H.B., N.D., R.F., I.K., P.N., C.A.L.R., G.S., C.v.G., R.N.-E. and C.G. clinically characterized TAR cases. C.A.A., K.F., W.H.O. and C.G. wrote the manuscript.
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Albers, C., Paul, D., Schulze, H. et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 44, 435–439 (2012). https://doi.org/10.1038/ng.1083
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DOI: https://doi.org/10.1038/ng.1083
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