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Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome

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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Figure 1: Most TAR syndrome cases have a low-frequency regulatory variant and a rare null allele at the RBM8A locus.
Figure 2: Effect of the regulatory SNPs on transcription factor binding, RBM8A promoter activity and protein expression in platelets.

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References

  1. Kim, V.N., Kataoka, N. & Dreyfuss, G. Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex. Science 293, 1832–1836 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Le Hir, H., Gatfield, D., Izaurralde, E. & Moore, M.J. The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J. 20, 4987–4997 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lykke-Andersen, J., Shu, M.-D. & Steitz, J.A. Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293, 1836–1839 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Palacios, I.M., Gatfield, D., St Johnston, D. & Izaurralde, E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Wiegand, H.L., Lu, S. & Cullen, B.R. Exon junction complexes mediate the enhancing effect of splicing on mRNA expression. Proc. Natl. Acad. Sci. USA 100, 11327–11332 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hall, J.G. et al. Thrombocytopenia with absent radius (TAR). Medicine (Baltimore) 48, 411–439 (1969).

    Article  CAS  Google Scholar 

  7. Klopocki, E. et al. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am. J. Hum. Genet. 80, 232–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Geddis, A.E. Inherited thrombocytopenia: congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Semin. Hematol. 43, 196–203 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Greenhalgh, K.L. et al. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J. Med. Genet. 39, 876–881 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Soranzo, N. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182–1190 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. The 1000 Genomes Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  12. Firmann, M. et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc. Disord. 8, 6 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  13. The ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

  14. Paul, D.S. et al. Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits. PLoS Genet. 7, e1002139 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Salicioni, A.M. et al. Identification and structural analysis of human RBM8A and RBM8B: two highly conserved RNA-binding motif proteins that interact with OVCA1, a candidate tumor suppressor. Genomics 69, 54–62 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Haremaki, T., Sridharan, J., Dvora, S. & Weinstein, D.C. Regulation of vertebrate embryogenesis by the exon junction complex core component Eif4a3. Dev. Dyn. 239, 1977–1987 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nicholson, P. et al. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol. Life Sci. 67, 677–700 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Weischenfeldt, J. et al. NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements. Genes Dev. 22, 1381–1396 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Perkins, A.S., Mercer, J.A., Jenkins, N.A. & Copeland, N.G. Patterns of Evi-1 expression in embryonic and adult tissues suggest that Evi-1 plays an important regulatory role in mouse development. Development 111, 479–487 (1991).

    CAS  PubMed  Google Scholar 

  21. Edery, P. et al. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332, 240–243 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. He, H. et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332, 238–240 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tarpey, P.S. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat. Genet. 39, 1127–1133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Coffey, A.J. et al. The GENCODE exome: sequencing the complete human exome. Eur. J. Hum. Genet. 19, 827–831 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Albers, C.A. et al. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat. Genet. 43, 735–737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tijssen, M.R. et al. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev. Cell 20, 597–609 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu, T.D. & Nacu, S. Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26, 873–881 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Robinson, J.T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Giresi, P.G. & Lieb, J.D. Isolation of active regulatory elements from eukaryotic chromatin using FAIRE (Formaldehyde Assisted Isolation of Regulatory Elements). Methods 48, 233–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Morgan, M. et al. ShortRead: a Bioconductor package for input, quality assessment, and exploration of high throughput sequence data. Bioinformatics 25, 2607–2609 (2011).

    Article  Google Scholar 

  31. Lawrence, M., Gentleman, R. & Carey, V. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics 25, 1841–1842 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cartharius, K. et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21, 2933–2942 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Freson, K. et al. 391 C to G substitution in the regulator of G-protein signalling-2 promoter increases susceptibility to the metabolic syndrome in white European men: consistency between molecular and epidemiological studies. J. Hypertens. 25, 117–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Freson, K. et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98, 85–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Gnatenko, D.V. et al. Transcript profiling of human platelets using microarray and serial analysis of gene expression. Blood 101, 2285–2293 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Watkins, N.A. et al. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 113, e1–e9 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Contributions

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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Correspondence to Cornelis A Albers or Cedric Ghevaert.

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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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