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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
- Source :
- 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
- Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 10614036
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....461f96d420b521d87d5990f360e84678