Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families

Lisa Mirabello, Elizabeth R. Macari, Lea Jessop, Steven R. Ellis, Timothy Myers, Neelam Giri, Alison M. Taylor, Katherine E. McGrath, Jessica M. Humphries, Bari J. Ballew, Meredith Yeager, Joseph F. Boland, Ji He, Belynda D. Hicks, Laurie Burdett, Blanche P. Alter, Leonard Zon, Sharon A. Savage

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)24-32
Number of pages9
Issue number1
StatePublished - Jul 3 2014
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)


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