Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families.
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.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Lisa
L
Mirabello
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA;
Elizabeth R
ER
Macari
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Lea
L
Jessop
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY;
Steven R
SR
Ellis
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Timothy
T
Myers
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Neelam
N
Giri
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA;
Alison M
AM
Taylor
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA;
Katherine E
KE
McGrath
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA;
Jessica M
JM
Humphries
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Bari J
BJ
Ballew
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
Meredith
M
Yeager
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
Joseph F
JF
Boland
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
Ji
J
He
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
Belynda D
BD
Hicks
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
Laurie
L
Burdett
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Blanche P
BP
Alter
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA.
Leonard
L
Zon
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD;
Sharon A
SA
Savage
D017668:Age of Onset; D000595:Amino Acid Sequence; D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics*; D015027:Zebrafish
D012269:Ribosomal Proteins; C079855:ribosomal protein S29