Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations.
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.


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.
Hematology Unit, Pediatric Department, University of Torino Piazza Polonia 94, 10126 Torino, Italy.
Paola
P
Quarello
Emanuela
E
Garelli
Adriana
A
Carando
Alfredo
A
Brusco
Roberto
R
Calabrese
Carlo
C
Dufour
Daniela
D
Longoni
Aldo
A
Misuraca
Luciana
L
Vinti
Anna
A
Aspesi
Laura
L
Biondini
Fabrizio
F
Loreni
Irma
I
Dianzani
Ugo
U
Ramenghi
D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D015331:Cohort Studies; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007558:Italy; D009154:Mutation; D010641:Phenotype; D012269:Ribosomal Proteins / Q000235:genetics*
D012269:Ribosomal Proteins; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human