BACKGROUND: Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. DESIGN AND METHODS: In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. RESULTS: About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. CONCLUSIONS: Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.
BACKGROUND: Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. DESIGN AND METHODS: In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. RESULTS: About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. CONCLUSIONS: Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.
Authors: T N Willig; C M Niemeyer; T Leblanc; C Tiemann; A Robert; J Budde; A Lambiliotte; E Kohne; G Souillet; S Eber; J L Stephan; R Girot; P Bordigoni; G Cornu; S Blanche; J M Guillard; N Mohandas; G Tchernia Journal: Pediatr Res Date: 1999-11 Impact factor: 3.756
Authors: Hanna T Gazda; Agnieszka Grabowska; Lilia B Merida-Long; Elzbieta Latawiec; Hal E Schneider; Jeffrey M Lipton; Adrianna Vlachos; Eva Atsidaftos; Sarah E Ball; Karen A Orfali; Edyta Niewiadomska; Lydie Da Costa; Gil Tchernia; Charlotte Niemeyer; Joerg J Meerpohl; Joachim Stahl; Gerhard Schratt; Bertil Glader; Karen Backer; Carolyn Wong; David G Nathan; Alan H Beggs; Colin A Sieff Journal: Am J Hum Genet Date: 2006-11-02 Impact factor: 11.025
Authors: Jason E Farrar; Michelle Nater; Emi Caywood; Michael A McDevitt; Jeanne Kowalski; Clifford M Takemoto; C Conover Talbot; Paul Meltzer; Diane Esposito; Alan H Beggs; Hal E Schneider; Agnieszka Grabowska; Sarah E Ball; Edyta Niewiadomska; Colin A Sieff; Adrianna Vlachos; Eva Atsidaftos; Steven R Ellis; Jeffrey M Lipton; Hanna T Gazda; Robert J Arceci Journal: Blood Date: 2008-06-05 Impact factor: 22.113
Authors: T N Willig; N Draptchinskaia; I Dianzani; S Ball; C Niemeyer; U Ramenghi; K Orfali; P Gustavsson; E Garelli; A Brusco; C Tiemann; J L Pérignon; C Bouchier; L Cicchiello; N Dahl; N Mohandas; G Tchernia Journal: Blood Date: 1999-12-15 Impact factor: 22.113
Authors: Leana Doherty; Mee Rie Sheen; Adrianna Vlachos; Valerie Choesmel; Marie-Françoise O'Donohue; Catherine Clinton; Hal E Schneider; Colin A Sieff; Peter E Newburger; Sarah E Ball; Edyta Niewiadomska; Michal Matysiak; Bertil Glader; Robert J Arceci; Jason E Farrar; Eva Atsidaftos; Jeffrey M Lipton; Pierre-Emmanuel Gleizes; Hanna T Gazda Journal: Am J Hum Genet Date: 2010-01-28 Impact factor: 11.025