Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond–Blackfan anemia
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Diamond–Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30–50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60–65 % of patients. Here, we report a novel large deletion in RPL15, a gene not previously implicated to be causative in DBA. Like RPL26, RPL15 presents the distinctive feature of being required both for 60S subunit formation and for efficient cleavage of the internal transcribed spacer 1. In addition, we detected five deletions in RP genes in which mutations have been previously shown to cause DBA: one each in RPS19, RPS24, and RPS26, and two in RPS17. Pre-ribosomal RNA processing was affected in cells established from the patients bearing these deletions, suggesting a possible molecular basis for their pathological effect. These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients.
KeywordsRibosomal Protein Gene Erythroid Differentiation Macrocytic Anemia aCGH Analysis Copy Number Assay
We wish to thank the patients and their families for participating in the study. This work was supported by the following Grants: NIH Grants R01 HL107558 and K02 HL111156, a Grant from the DBA Foundation (to H.T.G.), and a Grant from the Agence Nationale de la Recherche (RIBOCRASH) (to P.E.G.).
Conflict of interest
The authors declare that they have no conflict of interest.
- Doherty L, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Clinton C, Schneider HE, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Glader B, Arceci RJ, Farrar JE, Atsidaftos E, Lipton JM, Gleizes PE, Gazda HT (2010) Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond–Blackfan anemia. Am J Hum Genet 86:222–228PubMedCrossRefGoogle Scholar
- Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, Talbot CC Jr, Meltzer P, Esposito D, Beggs AH, Schneider HE, Grabowska A, Ball SE, Niewiadomska E, Sieff CA, Vlachos A, Atsidaftos E, Ellis SR, Lipton JM, Gazda HT, Arceci RJ (2008) Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond–Blackfan anemia. Blood 112:1582–1592PubMedCrossRefGoogle Scholar
- Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH, Sieff CA (2006) Ribosomal protein S24 gene is mutated in Diamond–Blackfan anemia. Am J Hum Genet 79:1110–1118PubMedCrossRefGoogle Scholar
- Gazda HT, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH (2008) Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond–Blackfan anemia patients. Am J Hum Genet 83:769–780PubMedCrossRefGoogle Scholar
- Gazda HT, Preti M, Sheen MR, O’Donohue MF, Vlachos A, Davies SM, Kattamis A, Doherty L, Landowski M, Buros C, Ghazvinian R, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Glader B, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH (2012) Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in Diamond–Blackfan anemia. Hum Mutat 33:1037–1044PubMedCrossRefGoogle Scholar
- Idol RA, Robledo S, Du HY, Crimmins DL, Wilson DB, Ladenson JH, Bessler M, Mason PJ (2007) Cells depleted for RPS19, a protein associated with Diamond Blackfan anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis 39:35–43PubMedCrossRefGoogle Scholar
- Kuramitsu M, Sato-Otsubo A, Morio T, Takagi M, Toki T, Terui K, Wang R, Kanno H, Ohga S, Ohara A, Kojima S, Kitoh T, Goi K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I (2012) Extensive gene deletions in Japanese patients with Diamond–Blackfan anemia. Blood 119:2376–2384PubMedCrossRefGoogle Scholar
- Quarello P, Garelli E, Brusco A, Carando A, Mancini C, Pappi P, Vinti L, Svahn J, Dianzani I, Ramenghi U (2012) High frequency of ribosomal protein gene deletions in Italian Diamond Blackfan anemia patients detected by multiplex ligation-dependent probe amplification (MLPA) assay. Haematologica 97:1813–1817PubMedCrossRefGoogle Scholar
- Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM (2008) Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 142:859–876PubMedCrossRefGoogle Scholar
- Willig TN, Niemeyer CM, Leblanc T, Tiemann C, Robert A, Budde J, Lambiliotte A, Kohne E, Souillet G, Eber S, Stephan JL, Girot R, Bordigoni P, Cornu G, Blanche S, Guillard JM, Mohandas N, Tchernia G (1999) Identification of new prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond–Blackfan anemia patients. DBA group of Societe d’Hematologie et d’Immunologie Pediatrique (SHIP), Gesellshaft fur Padiatrische Onkologie und Hamatologie (GPOH), and the European Society for Pediatric Hematology and Immunology (ESPHI). Pediatr Res 46:553–561PubMedCrossRefGoogle Scholar