The ribosomal basis of diamond-blackfan anemia: mutation and database update

Abstract

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.

High frequency of ribosomal protein gene deletions in Italian Diamond-Blackfan anemia patients detected by multiplex ligation-dependent probe amplification assay

“…2,3 The major DBA gene, ribosomal protein (RP) S19 4 is mutated in approximately 25% of patients. 5 Heterozygous mutations in an increasing number of other genes encoding RPs of the small (RPS7, RPS10, RPS17, RPS24, RPS26) or the large (RPL5, RPL11, RPL35A) ribosomal subunits have been reported in DBA patients. [5][6][7][8][9][10][11] However, point mutations in the coding regions of these genes are present in only 50% of DBA patients, as shown by a series of sequencing studies that also included a screening of almost all RP genes.…”

“…5 Heterozygous mutations in an increasing number of other genes encoding RPs of the small (RPS7, RPS10, RPS17, RPS24, RPS26) or the large (RPL5, RPL11, RPL35A) ribosomal subunits have been reported in DBA patients. [5][6][7][8][9][10][11] However, point mutations in the coding regions of these genes are present in only 50% of DBA patients, as shown by a series of sequencing studies that also included a screening of almost all RP genes. 5,8,10 This suggests that DBA has a further genetic heterogeneity due to non-RP genes or that there are also other mutations besides those detected by traditional sequencing.…”

Guidelines for establishing locus specific databases

“…For more common disorders, one strategy is being implemented by Human Mutation. The authors of "Mutation Updates" (for e.g., see [Boria et al, 2010]) are encouraged to contact labs worldwide, that are working on the gene in question, to request that they submit mutations in return for authorship. Nature Genetics also has this policy under the banner of microattribution [Giardine et al, 2011].…”

Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families

“…1 It is characterized by red blood cell (RBC) aplasia and variable congenital anomalies. DBA classically presents with severe anemia in the first year of life and may include craniofacial anomalies such as flat nasal bridge, high arched or cleft palate, and short stature.…”

“…7,8 Germ-line mutations in genes encoding components of both the small (RPS24, RPS17, RPS7, RPS10, and RPS26) and large (RPL35A, RPL5, RPL11, and RPL26) ribosomal subunits have also been described in DBA patients. 1,9,10 Recently, mutations in the GATA1 gene, an X-linked hematopoietic transcription factor, were found to cause DBA in a minority of patients. 11 However, because GATA1 has been implicated in DBA, 11 it is possible that non-RP genes may also lead to the characteristic erythroid hypoplasia.…”