Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome
| Autor: | K Smith, Chantal Thys, Najet Debili, Paul Bertone, Paquita Nurden, Gabriele Strauss, Kathleen Freson, Rémi Favier, Jennifer Jolley, Cornelis A. Albers, Jennifer G. Sambrook, Dirk S. Paul, Myrto Kostadima, Ingrid P.C. Krapels, Matthew E. Hurles, Graham Kiddle, Derek L. Stemple, Jonathan Stephens, Catherine M. Hobbs, Ana Cvejic, Janine Fiedler, Willem H. Ouwehand, Christel Van Geet, Cedric Ghevaert, Claudia A. L. Ruivenkamp, Panos Deloukas, Martijn H. Breuning, Ni Huang, Ruth Newbury-Ecob, Peter A. Smethurst, Harald Schulze |
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| Přispěvatelé: | MUMC+: DA KG Polikliniek (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Adolescent Protein subunit Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Article Frameshift mutation Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] Young Adult 03 medical and health sciences 0302 clinical medicine Transcription (biology) Genetics medicine Animals Congenital Bone Marrow Failure Syndromes Humans Genetic Predisposition to Disease Amino Acid Sequence Upper Extremity Deformities Congenital Child Zebrafish 030304 developmental biology 0303 health sciences Base Sequence Platelet Count TAR syndrome Infant Newborn Genetic Variation Infant RNA-Binding Proteins Sequence Analysis DNA medicine.disease Thrombocytopenia Molecular biology Null allele Radius Regulatory sequence Child Preschool 030220 oncology & carcinogenesis Mutation Exon junction complex Female 5' Untranslated Regions Sequence Alignment |
| Zdroj: | Nature Genetics, 44(4), 435-U248 Nature Genetics, 44, 435-9, S1-2 Nature Genetics, 44(4), 435-U248. Nature Publishing Group Nature Genetics, 44, 4, pp. 435-9, S1-2 Nature genetics |
| ISSN: | 1061-4036 |
| Popis: | Item does not contain fulltext The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), 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, 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. |
| Databáze: | OpenAIRE |
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