Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families
Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families
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DOI：
10.1182/blood-2013-11-540278
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发表时间：
2014-07-03
期刊：
影响因子：
20.3
通讯作者：
Savage, Sharon A.
中科院分区：
文献类型：
--
作者：
Mirabello, Lisa;Macari, Elizabeth R.;Savage, Sharon A.
Diamond-Blackfan贫血（DBA）是一种易患癌症的遗传性骨髓衰竭综合征。大约一半的DBA患者的核糖体蛋白基因存在种系突变。我们使用全外显子组测序来鉴定2个DBA大家族中的致病基因。筛选后，核糖体蛋白S29（RPS 29 [AUC 1]）基因中的1个非同义突变（p.I31F）存在于所有5个DBA受影响的个体和专性携带者中，而在1个DBA家族中未受影响的非携带者父母中不存在。发现第二个DBA家族在RPS 29中具有不同的非同义突变（p.I50T）。两种突变都是外显子2中的氨基酸取代，预测是有害的，并且与来自未受影响的对照的野生型RPS 29表达相比，导致RPS 29表达的单倍不足。与健康对照相比，具有p.I31F RPS 29突变的DBA先证者具有前核糖体RNA（rRNA）加工缺陷。我们证明了在rps 29（-/-）突变斑马鱼DBA模型中，两种Rps 29突变都不能挽救有缺陷的红细胞生成。RPS 29是核糖体小40 S亚基的组成部分，对rRNA加工和核糖体生物合成至关重要。我们发现了一个新的DBA致病基因，RPS 29，并表明生殖系突变RPS 29可以导致有缺陷的红细胞生成表型使用斑马鱼模型。
Diamond-Blackfan anemia (DBA) is a cancer-prone inherited bone marrow failure syndrome. Approximately half of DBA patients have a germ-line mutation in a ribosomal protein gene. We used whole-exome sequencing to identify disease-causing genes in 2 large DBA families. After filtering, 1 nonsynonymous mutation (p.I31F) in the ribosomal protein S29 (RPS29[AUQ1]) gene was present in all 5 DBA-affected individuals and the obligate carrier, and absent from the unaffected noncarrier parent in 1 DBA family. A second DBA family was found to have a different nonsynonymous mutation (p.I50T) in RPS29. Both mutations are amino acid substitutions in exon 2 predicted to be deleterious and resulted in haploinsufficiency of RPS29 expression compared with wild-type RPS29 expression from an unaffected control. The DBA proband with the p.I31F RPS29 mutation had a pre-ribosomal RNA (rRNA) processing defect compared with the healthy control. Wedemonstrated that both RPS29 mutations failed to rescue the defective erythropoiesis in the rps29(-/-) mutant zebra fish DBA model. RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis. We uncovered a novel DBA causative gene, RPS29, and showed that germ-line mutations in RPS29 can cause a defective erythropoiesis phenotype using a zebra fish model.