A new database for ribosomal protein genes which are mutated in Diamond-Blackfan Anemia

Abstract

Mutations in ribosomal proteins RPS19, RPS24 and RPS17 have been reported in DiamondBlackfan Anemia (DBA), an autosomal dominant disease characterised by pure red cell aplasia. DBA is the prototype of ribosomapathies: a protein synthesis defect in a tissue with a high cellular turnover is considered the cause of the erythroid progenitor failure. We have created the Diamond-Blackfan Anemia mutation database to curate and record DBA gene mutations, together with their functional consequences and clinical phenotypes. This locusspecific resource is open to future submissions and is available online (http://www.dbagenes.unito.it). It is founded on the Leiden Open (source) Variation Database (LOVD) system and includes data from sequence and structure analysis tools, genomic database resources and published reports. It lists all identified variants and background genomic information. Phenotypic data are accessed by selecting a particular mutation. The database includes 219 unique variants of which 86 are disease-causing mutations. The database will be supplemented with other DBA genes as soon as they are reported and their mutations are identified and it should be of assistance to clinicians and investigators involved in DBA research and care.© 2008 Wiley-Liss, Inc.KEY WORDS: Diamond-Blackfan Anemia, ribosomal protein, erythropoiesis, ribosome biogenesis. INTRODUCTIONDiamond-Blackfan anemia (DBA; MIM# 105650) is a pure red cell aplasia of childhood with an incidence ranging from 5 to 10 cases per million live births in Europe [Campagnoli et al., 2004]. Its main clinical features are normochromic and macrocytic anemia, reticulocytopenia and hypoplasia of erythroid progenitors in the bone marrow, whereas other hematopoietic lineages are usually normal [Campagnoli et al., 2004]. About 30% of patients display somatic abnormalities, involving the upper limbs, head, neck, the urogenital and cardiovascular systems, along with growth retardation. Patients have an increased risk of malignancies [Campagnoli et al., 2004;Lipton et al., 2001]. Management begins with corticosteroids, though the response is variable. Non-responders require multiple blood transfusions. Allogeneic bone marrow or stem cells transplantation is the only curative treatment at present [Roy et al., 2005;Lipton et al., 2006].Ribosomal protein (RP) S19 was the only gene associated with DBA for several years. It is mutated in 25% of patients with either sporadic or familial DBA, always in heterozygosity [Draptchinskaia et al., 1999;Campagnoli et al., 2008]. Mutations in RPS24 have been identified in 3/215 (~2%) DBA probands [Gazda et al., 2006] RPS17 mutation was reported in 1/24 [Cmejla et al., 2007]. Mutations in RPL35A [Farrar et al., 2007], RPL11 and RPL5 have been described, but not yet published in extenso. DBA is thus the only known human disease caused by an RP deficiency and is the prototype of ribosomapathies [Luzzatto and Karadimitris, 1998].The RPS19 gene (MIM# 603474) maps on locus 19q13.2, comprises six exons and spans 11 kb. The first exon (3...

Translation factors and ribosomal proteins control tumor onset and progression: how?

“…For instance, there is a clear association between oral cleft abnormalities and mutations of RPL5, 138 whereas this phenotype has not been reported in more than 120 RPS19-mutated patients analyzed in another study. 139 Although other explanations are possible (see below), these findings could indicate that ribosomes lacking specific ribosomal proteins (RPs) can have different translation specificity. A similar conclusion is proposed by Horos et al 140 in the analysis of an in vitro DBA experimental model.…”

Clinical utility gene card for: Diamond – Blackfan Anemia – update 2013

“…10 Mutations resulting in haploinsufficiency or loss-of-function in all 10 genes thus far described include missense mutations, nonsense mutations, splice mutations, insertions, deletions and rearrangements. 11,12 Recently mutations in the erythroid transcription regulator GATA1, apparently not involving any disruption in ribosome biogenesis/function, have been discovered as causative in rare cases of X-linked clinical DBA. 13 …”

Clinical utility gene card for: Diamond Blackfan anemia

“…[2][3][4][5][6][7] Mutations resulting in haploinsufficiency or loss of function in all nine genes thus far described include missense mutations, nonsense mutations, splice mutations, insertions, deletions and rearrangements. 8,9 1.6 Analytical methods Depending on the nature and magnitude of the sequence change a variety of techniques are available: cytogenetics for large deletions and rearrangements, multiple ligation dependent analysis (MLPA) for detection of large deletions and rearrangements, array comparative genomic hybridization (CGH) for detection of deletions, quantitative PCR and genomic sequencing. It is estimated that B10% of RPS19 haploinsufficient DBA cases are caused by large deletions that are missed by exon sequencing.…”