Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia

被引：179

作者：

Farrar, Jason E. ^{[1
]}

Nater, Michelle ^{[1
]}

Caywood, Emi ^{[1
]}

McDevitt, Michael A. ^{[2
]}

Kowalski, Jeanne ^{[3
]}

Takemoto, Clifford M. ^{[4
]}

Talbot, C. Conover, Jr. ^{[5
]}

Meltzer, Paul ^{[6
]}

Esposito, Diane ^{[7
]}

Beggs, Alan H. ^{[8
,9
,10
]}

Schneider, Hal E. ^{[8
,9
]}

Grabowska, Agnieszka ^{[8
,9
]}

Ball, Sarah E. ^{[11
]}

Niewiadomska, Edyta ^{[12
]}

Sieff, Colin A. ^{[10
,13
,14
]}

Vlachos, Adrianna ^{[15
]}

Atsidaftos, Eva ^{[15
]}

Ellis, Steven R. ^{[16
]}

Lipton, Jeffrey M. ^{[15
]}

Gazda, Hanna T. ^{[8
,9
,10
]}

Areci, Robert J. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Dept Oncol,Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Sch Med, Div Hematol, Dept Med, Baltimore, MD USA

[3] Johns Hopkins Univ, Sch Med, Div Oncol Biostat, Dept Oncol,Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[4] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Dept Pediat, Baltimore, MD USA

[5] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA

[6] Natl Human Genome Res Inst, Canc Genet Branch, Natl Inst Hlth, Bethesda, MD USA

[7] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[8] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[9] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Boston, MA USA

[11] Univ London St Georges Hosp, Dept Cellular & Mol Med, London, England

[12] Univ Med Sch, Dept Pediat Hematol Oncol, Warsaw, Poland

[13] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[14] Childrens Hosp, Div Pediat Hematol, Boston, MA 02115 USA

[15] Schneider Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY USA

[16] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA

来源：

BLOOD | 2008年 / 112卷 / 05期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1182/blood-2008-02-140012

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rp135a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.

引用

页码：1582 / 1592

页数：11

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