The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update.
Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.
Department of Medical Sciences, and IRCAD Università del Piemonte Orientale A. Avogadro, Alessandria, Novara, Vercelli, Italy.
Ilenia
I
Boria
Emanuela
E
Garelli
Hanna T
HT
Gazda
Anna
A
Aspesi
Paola
P
Quarello
Elisa
E
Pavesi
Daniela
D
Ferrante
Joerg J
JJ
Meerpohl
Mutlu
M
Kartal
Lydie
L
Da Costa
Alexis
A
Proust
Thierry
T
Leblanc
Maud
M
Simansour
Niklas
N
Dahl
Anne-Sophie
AS
Fröjmark
Dagmar
D
Pospisilova
Radek
R
Cmejla
Alan H
AH
Beggs
Mee R
MR
Sheen
Michael
M
Landowski
Christopher M
CM
Buros
Catherine M
CM
Clinton
Lori J
LJ
Dobson
Adrianna
A
Vlachos
Eva
E
Atsidaftos
Jeffrey M
JM
Lipton
Steven R
SR
Ellis
Ugo
U
Ramenghi
Irma
I
Dianzani
D029503:Anemia, Diamond-Blackfan / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D030541:Databases, Genetic; D056726:Genetic Association Studies; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics; D012270:Ribosomes / Q000235:genetics*
D012269:Ribosomal Proteins