2. Academic Validation
  3. 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

  • Blood. 2014 Jul 3;124(1):24-32. doi: 10.1182/blood-2013-11-540278.
Lisa Mirabello 1,  Elizabeth R Macari 2,  Lea Jessop 1,  Steven R Ellis 3,  Timothy Myers 1,  Neelam Giri 1,  Alison M Taylor 2,  Katherine E McGrath 2,  Jessica M Humphries 2,  Bari J Ballew 1,  Meredith Yeager 4,  Joseph F Boland 4,  Ji He 4,  Belynda D Hicks 4,  Laurie Burdett 4,  Blanche P Alter 1,  Leonard Zon 5,  Sharon A Savage 1
Affiliations

Affiliations

  • 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
  • 2 Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA;
  • 3 Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY;
  • 4 Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
  • 5 Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA.
PMID: 24829207 DOI: 10.1182/blood-2013-11-540278
Abstract

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. We demonstrated 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.

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