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

Oleh:

Albers, Cornelis A ; Paul, Dirk S ; Schulze, Harald

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Nature Genetics vol. 44 no. 04 (Apr. 2012), page 435–439.

Ketersediaan

Perpustakaan FK Nomor Panggil: N12.K.2012.01 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

Lihat Detail Induk

Isi artikel

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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