Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia

Kuramitsu, Madoka; Sato‐Otsubo, Aiko; Morio, Tomohiro; Takagi, Motoki; Toki, Tsutomu; Terui, Kiminori; Wang, Ru Nan; Kanno, Hitoshi; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji; Kitoh, Toshiyuki; Goi, Kumiko; Kudo, Kazuko; Matsubayashi, Tadashi; Mizue, Nobuo; Ozeki, Michio; Masumi, Atsuko; Momose, Haruka; Takizawa, Kazuya; Mizukami, Tamio; Yamaguchi, Kazunari; Ogawa, Seishi; Ito, Etsuro; Hamaguchi, Isao

doi:10.1182/blood-2011-07-368662

Cited by 51 publications

(52 citation statements)

References 21 publications

(36 reference statements)

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“…As haploinsufficiency of RUNX1 might cause familial thrombocytopenia with propensity to develop AML 1 , we also examined whether the pedigrees have RUNX1 loss of heterozygosity (LOH) or not. A synchronized quantitative-PCR method 6 and single-nucleotide polymorphism (SNP) sequencing detected no case with LOH in RUNX1 in our cohort (Supplementary Fig. 1 and detailed in Methods).…”

Section: Resultsmentioning

confidence: 72%

Recurrent CDC25C mutations drive malignant transformation in FPD/AML

et al. 2014

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Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.

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Section: Resultsmentioning

confidence: 72%

Recurrent CDC25C mutations drive malignant transformation in FPD/AML

et al. 2014

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“…However, approximately 50% of DBA cases have as-yet-unidentified molecular mutations, despite systematic sequencing of all ribosomal protein and other candidate genes in these cases (1,2,4,5). Recent work has highlighted the role of deletions of ribosomal protein genes that may be responsible for a subset of cases without previously identified mutations (6,7). However, it is clear that the molecular etiology of many DBA cases remains to be uncovered.…”

Section: Introductionmentioning

confidence: 98%

Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia

Sankaran

Ghazvinian²,

Do³

et al. 2012

J. Clin. Invest.

305

323

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Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis.

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“…We previously used the multiplex ligation-dependent probe amplification (MLPA) technique to detect RPS19 gene deletions or duplications. [13][14][15] In order to better characterize the molecular defect in our cohort of Italian DBA patients who were negative for RP gene mutations by standard sequencing, we developed an MLPA synthetic probe set that allows the concurrent analysis of the six principal RP genes: RPS19, RPL5, RPL11, RPL35A, RPS17 and RPS26.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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© F e r r a t a S t o r t i F o u n d a t i o nThe finding of partial or complete RP deletions/duplications in DBA patients using CGH array, SNP array or quantitative PCR has been recently reported. [13][14][15] In order to better characterize the molecular defect in our cohort of Italian DBA patients who were negative for RP gene mutations by standard sequencing, we developed an MLPA synthetic probe set that allows the concurrent analysis of the six principal RP genes: RPS19, RPL5, RPL11, RPL35A, RPS17 and RPS26. Design and Methods PatientsPatients were selected from the Italian DBA Registry that includes 173 Italian subjects from 162 families. Diagnosis was reached following the criteria suggested by the DBA International Clinical Consensus (ICC) Consortium.2 All the patients were screened for mutations in ten genes.RPS19 mutations were found in 44 of 162 (27%) unrelated DBA patients using a strategy that included sequencing and the MLPA technique. The sequencing analysis of RPS24, RPS26, RPL5, and RPL11, revealed mutations in 46 of 162 (28%) unrelated patients. No mutations were found in RPS10, RPS14, RPS16, RPS17, or RPL35A. Seventy-two (45%) unrelated DBA patients showed no mutations in these genes and were included in this study. Informed consent was obtained from all patients and/or their legal guardians. MLPA design and methodMLPA oligonucleotide probes were designed according to the "Designing synthetic MLPA probes" protocol v.8 (MRC-Holland, Amsterdam, The Netherlands) that uses 12 probes per assay. Each synthetic probe was composed of two 5′ and 3′ half-probes containing unique target-specific sequence and universal primer sequences 5′-GGGTTCCCTAAGGGTTGGA and 5′-TCTA-GATTGGATCTTGCTGGCAC on their 5′ and 3′ ends, respectively. Primers were designed in regions that did not include single nucleotide polymorphisms (SNPs) (http://genome.ucsc.edu/).Because of the constraint of including 12 probes, we were forced to choose a strategy aimed at the screening of whole gene deletions or duplications. The probemix contained probes interrogating 1-3 exons per each RP gene (Online Supplementary Table S1, Figure 1A and B).MLPA was performed on genomic DNA according to the manufacturer's instructions. We used the P200-A1 Human DNA reference kit that includes reference probes and MLPA control fragments (http://www.mrc-holland.com).The PCR products were diluted 1:15 in water, 1 mL of this solution was mixed with 10 mL of HiDi formamide (ABI) and 0.2 mL of ROX500 size standard. The amplification products were separated by capillary electrophoresis on an ABI 3100 Avant Genetic Analyzer (Applied Biosystems, Warrington, UK). Genescan v3.7 software was used to analyze the runs and to retrieve peak intensities corresponding to each probe in the different samples and the integrated peak areas were exported to an Excel 2003 spreadsheet (Microsoft, CA, USA).Normalization was obtained by dividing the peak area of each probe's amplification product by the combined peak areas of all probes (intra-normalization). We then ...

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Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia

Cited by 51 publications

References 21 publications

Recurrent CDC25C mutations drive malignant transformation in FPD/AML

Recurrent CDC25C mutations drive malignant transformation in FPD/AML

Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia

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

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