| Autor: |
Mirabello, Lisa, Macari, Elizabeth R., Jessop, Lea, Ellis, Steven R., Myers, Timothy, Giri, Neelam, Taylor, Alison M., McGrath, Katherine E., Humphries, Jessica M., Ballew, Bari J., Yeager, Meredith, Boland, Joseph F., He, Ji, Hicks, Belynda D., Burdett, Laurie, Alter, Blanche P., Zon, Leonard, Savage, Sharon A. |
| Zdroj: |
Blood; July 2014, Vol. 124 Issue: 1 p24-32, 9p |
| Abstrakt: |
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 RPS29expression compared with wild-type RPS29expression from an unaffected control. The DBA proband with the p.I31F RPS29mutation had a pre–ribosomal RNA (rRNA) processing defect compared with the healthy control. We demonstrated that both RPS29mutations failed to rescue the defective erythropoiesis in the rps29−/−mutant zebra fish DBA model. RPS29is 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 RPS29can cause a defective erythropoiesis phenotype using a zebra fish model. |
| Databáze: |
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