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.
Boria
Ilenia
I
Department of Medical Sciences, and IRCAD Università del Piemonte Orientale A. Avogadro, Alessandria, Novara, Vercelli, Italy.
Garelli
Emanuela
E
Gazda
Hanna T
HT
Aspesi
Anna
A
Quarello
Paola
P
Pavesi
Elisa
E
Ferrante
Daniela
D
Meerpohl
Joerg J
JJ
Kartal
Mutlu
M
Da Costa
Lydie
L
Proust
Alexis
A
Leblanc
Thierry
T
Simansour
Maud
M
Dahl
Niklas
N
Fröjmark
Anne-Sophie
AS
Pospisilova
Dagmar
D
Cmejla
Radek
R
Beggs
Alan H
AH
Sheen
Mee R
MR
Landowski
Michael
M
Buros
Christopher M
CM
Clinton
Catherine M
CM
Dobson
Lori J
LJ
Vlachos
Adrianna
A
Atsidaftos
Eva
E
Lipton
Jeffrey M
JM
Ellis
Steven R
SR
Ramenghi
Ugo
U
Dianzani
Irma
I
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