Exploiting pre‐rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis
Open Access
- 15 July 2014
- journal article
- research article
- Published by Wiley in American Journal of Hematology
- Vol. 89 (10), 985-991
- https://doi.org/10.1002/ajh.23807
Abstract
Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single‐copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre‐rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre‐rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre‐60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene. Am. J. Hematol. 89:985–991, 2014.Keywords
Funding Information
- National Institutes of Health (K08 HL092224)
- National Institutes of Health (R01 HL07957)
- Diamond Blackfan Anemia Foundation
- Fondazione Cariplo (2011-0554)
- Pediatric Cancer Foundation
- Fondazione Telethon (GGP13177)
- National Institutes of Health (R109 MOHLKE)
- National Human Genome Research Institute
- Arkansas Biosciences Institutes
- cariplo (2011-0554)
- Istituto Piemontese per la ricerca sulla Anemia di Diamond-Blackfan
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