Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia.
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 Rpl35a 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.
Farrar
Jason E
JE
Division of Pediatric Oncology, Department of Oncology, Kimmel Comprehensive Cancer Center.
Nater
Michelle
M
Caywood
Emi
E
McDevitt
Michael A
MA
Kowalski
Jeanne
J
Takemoto
Clifford M
CM
Talbot
C Conover
CC
Meltzer
Paul
P
Esposito
Diane
D
Beggs
Alan H
AH
Schneider
Hal E
HE
Grabowska
Agnieszka
A
Ball
Sarah E
SE
Niewiadomska
Edyta
E
Sieff
Colin A
CA
Vlachos
Adrianna
A
Atsidaftos
Eva
E
Ellis
Steven R
SR
Lipton
Jeffrey M
JM
Gazda
Hanna T
HT
Arceci
Robert J
RJ
D000595:Amino Acid Sequence; D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism
D034741:RNA, Small Interfering; C489281:RPL35A protein, human; D012269:Ribosomal Proteins; D004247:DNA