What’s in a name? Mitchell J. Weiss, … , Philip J. Mason, Monica Bessler J Clin Invest. 2012;122(7):2346-2349. https://doi.org/10.1172/JCI63989. Commentary Mutations in numerous genes encoding ribosomal proteins (RPs) occur in 50%–70% of individuals with Diamond- Blackfan anemia (DBA), establishing the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, Gazda, and colleagues used genome-wide exome sequencing to study DBA patients with no detectable mutations in RP genes. They identified two unrelated pedigrees in which the disease is associated with mutations in GATA1, which encodes an essential hematopoietic transcription factor with no known mechanistic links to ribosomes. These findings ignite an interesting and potentially emotional debate on how we define DBA and whether the term should be restricted to pure ribosomopathies. More generally, the work reflects the powerful knowledge and controversies arising from the deluge of data generated by new genetic technologies that are being used to analyze human diseases. Find the latest version: https://jci.me/63989/pdf commentaries ognized. While the authors’ findings on 949.824.5626; Fax: 949.824.8598; E-mail: 11. Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D. Detection of attenuated, noninfec- experimental infections of laboratory mice [email protected]. tious spirochetes in Borrelia burgdorferi-infect- may not change opinions on appropriate ed mice after antibiotic treatment. J Infect Dis. antibiotic therapy for patients, they point 1. Simpson J, Weiner E, eds. Oxford English Dictionary. 2002;186(10):1430–1437. to testable hypotheses on the mechanisms 2nd ed. Oxford, United Kingdom: Oxford Univer- 12. Domingue GJ Sr, Woody HB. Bacterial persis- sity Press; 1989. tence and expression of disease. 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Clin Rheumatol. 2012; Address correspondence to: Alan Barbour, Borrelia burgdorferi to metronidazole. APMIS. 31(6):989–994. Departments of Medicine and Microbiol- 1999;107(6):566–576. 20. Gutman LT, Turck M, Petersdorf RG, Wedgwood ogy & Molecular Genetics, University of 10. Straubinger RK, Summers BA, Chang YF, Appel RJ. Significance of bacterial variants in urine of MJ. Persistence of Borrelia burgdorferi in experi- patients with chronic bacteriuria. J Clin Invest. California Irvine, 3012 Hewitt Hall, Irvine, mentally infected dogs after antibiotic treatment. 1965;44(12):1945–1952. California 92697-4028, USA. Phone: J Clin Microbiol. 1997;35(1):111–116. What’s in a name? Mitchell J. Weiss, Philip J. Mason, and Monica Bessler The Children’s Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania, USA. Mutations in numerous genes encoding ribosomal proteins (RPs) occur in of chromosome 19 to DBA in a proportion 50%–70% of individuals with Diamond-Blackfan anemia (DBA), establishing of multiplex families (2). Positional cloning the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, revealed that the mutated gene was RPS19, Gazda, and colleagues used genome-wide exome sequencing to study DBA which encodes a protein component of the patients with no detectable mutations in RP genes. They identified two unre- small 40S ribosomal subunit (3). Subse- lated pedigrees in which the disease is associated with mutations in GATA1, quently, RPS19 mutations were identified which encodes an essential hematopoietic transcription factor with no known in approximately 25% of DBA families, all mechanistic links to ribosomes. These findings ignite an interesting and poten- of which showed dominant inheritance. tially emotional debate on how we define DBA and whether the term should be Speculation about how RPS19 mutations restricted to pure ribosomopathies. More generally, the work reflects the pow- might cause DBA ensued for about 10 years. erful knowledge and controversies arising from the deluge of data generated by Specifically, it was debated as to whether the new genetic technologies that are being used to analyze human diseases. disease results from loss of unique extra- ribosomal activities of RPS19 or through The history of DBA precursors and concomitant congenital impaired ribosome production. Support In 1938, pediatricians Louis Diamond and extrahematopoietic anomalies in about for the latter hypothesis emerged when a Kenneth Blackfan described a congenital one-third of patients (1). The etiology of flurry of other DBA genes were identified, anemia with hypoplasia of red blood cell this syndrome, now known as Diamond- all of which encoded different small or large Blackfan anemia (DBA), has fascinated and ribosomal subunit proteins (RPs) (4). perplexed pediatric hematologists for many Conflict of interest: The authors have declared that no conflict of interest exists. years. In 1997, Dahl and colleagues identi- DBA perceived as a ribosomopathy Citation for this article: J Clin Invest. 2012; fied a child with DBA and a X:19 chromo- Currently, 50%–70% of DBA patients are 122(7):2346–2349. doi:10.1172/JCI63989. somal translocation, linking a critical region accounted for by mutations in one of 2346 The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 7 July 2012 commentaries Figure 1 Current model for how RP haploinsufficiency causes DBA. (A) Normal erythroblasts produce large numbers of ribosomes for protein synthesis. Levels of p53 remain low via a feedback loop whereby MDM2, a transcriptional p53 target, ubiquitinates p53 to promote its degradation by pro- teasomes. (B) Haploinsufficiency for specific RPs causes accumulation of other RPs, which bind to MDM2, thereby inhibiting its ability to promote p53 degradation. Consequently, p53 accumulates and triggers cell cycle arrest and apoptosis. 10 RP genes (4, 5). Additional diseases the X chromosome–encoded GATA1 gene. GATA-1, a zinc finger transcription factor in which causative mutations impair By targeted sequencing of an additional 62 expressed mainly in blood cell precursors, is ribosomes include the inherited Treach- male DBA patients, all negative for RP gene essential for the development of red blood er-Collins and Shwachman-Diamond mutations, they identified a second family cells, megakaryocytes and their platelet syndromes and 5q- myelodysplastic syn- with an independent GATA1 gene muta- progeny, mast cells, and eosinophils (10). drome, caused by a somatic chromosomal tion. Both of these mutations alter mRNA Several human blood disorders are caused deletion (4). These disorders illustrate the splicing to favor the production of an by GATA1 mutations that partially reduce concept that genetic alterations in basic amino-truncated GATA-1 protein termed and/or alter function of the corresponding cellular pathways can produce unique GATA-1 short, or GATA-1s. protein (ref. 11 and Figure 2). Germline mis- combinations of organ-specific patholo- gies. How ribosome disruptions lead to DBA is not understood, but a popular theory is that imbalances in individual RPs trigger a p53-mediated checkpoint leading to cell cycle arrest and apoptosis of erythroid precursors (4). In support, certain RPs bind to and inhibit the p53 regulator MDM2 (6). Moreover, in animal models, the DBA-like effects of RP muta- tions depend in part on p53 (refs. 7, 8, Figure 2 and Figure 1).