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

被引：306

作者：

Albers, Cornelis A. ^{[1
,2
,3
]}

Paul, Dirk S. ^{[3
]}

Schulze, Harald ^{[4
,5
]}

Freson, Kathleen ^{[6
]}

Stephens, Jonathan C. ^{[1
,2
]}

Smethurst, Peter A. ^{[1
,2
]}

Jolley, Jennifer D. ^{[1
,2
]}

Cvejic, Ana ^{[1
,2
,3
]}

Kostadima, Myrto ^{[7
]}

Bertone, Paul ^{[7
]}

Breuning, Martijn H. ^{[8
]}

Debili, Najet ^{[9
]}

Deloukas, Panos ^{[3
]}

Favier, Remi ^{[9
]}

Fiedler, Janine ^{[5
,10
]}

Hobbs, Catherine M. ^{[1
,2
]}

Huang, Ni ^{[3
]}

Hurles, Matthew E. ^{[3
]}

Kiddle, Graham ^{[1
,2
]}

Krapels, Ingrid ^{[11
]}

Nurden, Paquita ^{[12
]}

Ruivenkamp, Claudia A. L. ^{[8
]}

Sambrook, Jennifer G. ^{[1
,2
]}

Smith, Kenneth ^{[13
,14
]}

Stemple, Derek L. ^{[3
]}

Strauss, Gabriele ^{[15
]}

Thys, Chantal ^{[6
]}

van Geet, Chris ^{[6
,16
]}

Newbury-Ecob, Ruth ^{[13
,14
]}

Ouwehand, Willem H. ^{[1
,2
,3
]}

Ghevaert, Cedric ^{[1
,2
]}

机构：

[1] Univ Cambridge, Dept Haematol, Cambridge, England

[2] Natl Hlth Serv NHS Blood & Transplant, Cambridge, England

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] Charite, Inst Transfus Med, D-13353 Berlin, Germany

[5] Charite, Lab Pediat Mol Biol, D-13353 Berlin, Germany

[6] Univ Leuven, Ctr Mol & Vasc Biol, Louvain, Belgium

[7] EBI, EMBL, Cambridge, England

[8] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands

[9] INSERM, U790, Villejuif, France

[10] Free Univ Berlin, Dept Biol Chem & Pharm, Berlin, Germany

[11] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands

[12] Hop Xavier Arnozan, Ctr Reference Pathol Plaquettaires, Hematol Lab, Pessac, France

[13] Univ Bristol, Div Child Hlth, Bristol, Avon, England

[14] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England

[15] Charite, Dept Pediat Oncol & Hematol, D-13353 Berlin, Germany

[16] Univ Ziekenhuis Leuven, Dept Pediat, Louvain, Belgium

来源：

NATURE GENETICS | 2012年 / 44卷 / 04期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

DEVELOPMENTAL DISORDER; THROMBOCYTOPENIA; BINDING; COMPONENT; GENE; EXPRESSION;

D O I：

10.1038/ng.1083

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：435 / U248

页数：7

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