Journal
NATURE GENETICS
Volume 44, Issue 4, Pages 435-U248Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.1083
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Funding
- National Institutes for Health Research (NIHR) [RP-PG-0310-1002, RBAG096]
- British Heart Foundation [FS/09/039, RG/09/12/28096]
- Wellcome Trust [WT-082597/Z/07/Z, WT-084183/2/07/2, WT091310]
- Deutsche Forschungsgemeinschaft [SCHU1421/3-1]
- Sanitatsrat Dr. Emil Alexander Hubner-und-Gemahlin-Stiftung [T114/17644/2008/sm]
- Excellentie Financiering KULeuven [EF/05/013]
- Fonds Wetenschappelijk Onderzoek-Vlaanderen [G.0490.10N, G.0743.09]
- Research Council of the University of Leuven (Onderzoeksraad-K.U. Leuven) [GOA/2009/13]
- Marie-Curie NetSim Initial Training Network [EC-215820]
- Gis-Maladies Rares, Diagnostic Differentiel des Purpuras Thrombopeniques Idiopathiques Chroniques et des Thrombopenies Congenitales (DIATROC)
- INSERM [ANR-08-GENO-028-03]
- National Institutes of Health Research (NIHR) [RP-PG-0310-1002] Funding Source: National Institutes of Health Research (NIHR)
- Wellcome Trust [082597/Z/07/Z] Funding Source: Wellcome Trust
- British Heart Foundation [FS/09/039/27788, RG/09/012/28096, RG/08/014/24067] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0310-1002] Funding Source: researchfish
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The exon-junction complex (EJC) performs essential RNA processing tasks(1-5). 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 x 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 TAR(7), 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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