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Tsutomu Toki,
Rika Kanezaki,
Eri Kobayashi,
Hiroshi Kaneko,
Mikiko Suzuki, Runan Wang,
Kiminori Terui,
Hirokazu Kanegane,
Miho Maeda,
Mikiya Endo,
Tatsuki Mizuochi,
Souichi Adachi,
Yasuhide Hayashi,
Masayuki Yamamoto,
Ritsuko Shimizu,
Etsuro Ito
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ABSTRACT: Down syndrome (DS) children have an increased incidence of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (AMKL). The majority of these cases harbor somatic mutations in the GATA1 gene, which results in the loss of full-length of GATA1, accordingly only a truncated isoform of GATA1 that lacks the N-terminal 83 amino acids (GATA1-S) remains. We found through genetic studies in 106 TAM patients that internally deleted GATA1 proteins (GATA1-IDs) lacking amino acid residues 77-119 or 74-88 (created by splicing mutations) contributed to the genesis of TAM in six patients. Analyses of GATA1-deficient embryonic megakaryocytic progenitors revealed that the GATA1 function in growth restriction was disrupted in GATA1-IDs. In contrast, GATA1-S rather promoted megakaryocyte proliferation more profoundly than that induced by GATA1-deficiency. These results indicate that the internally deleted regions play important roles in megakaryocyte proliferation and perturbation of this mechanism is involved in the pathogenesis of TAM.
Blood 02/2013; · 9.90 Impact Factor
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ABSTRACT: Diamond-Blackfan anemia (DBA) is an inherited bone marrow disease. The condition is characterized by anemia that usually presents during infancy or early childhood and congenital malformation. Several reports show that DBA is associated with mutations in the ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7. Recently, 5 and 12 patients with mutations in RPS10 and RPS26, respectively, were identified in a cohort of 117 DBA probands. Therefore, we screened the DBA patients who were negative for mutations in these DBA genes for mutations in RPS10 and RPS26. The present case report describes the identification of the first Japanese DBA patient with a novel mutation in RPS10.
Journal of Pediatric Hematology/Oncology 04/2012; 34(4):293-5. · 1.16 Impact Factor
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Rika Kanezaki,
Tsutomu Toki,
Kiminori Terui,
Gang Xu, Runan Wang,
Akira Shimada,
Asahito Hama,
Hirokazu Kanegane,
Kiyoshi Kawakami,
Mikiya Endo,
Daisuke Hasegawa,
Kazuhiro Kogawa,
Souichi Adachi,
Yasuhiko Ikeda,
Shotaro Iwamoto,
Takashi Taga,
Yoshiyuki Kosaka,
Seiji Kojima,
Yasuhide Hayashi,
Etsuro Ito
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ABSTRACT: Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.
Blood 11/2010; 116(22):4631-8. · 9.90 Impact Factor
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Yuki Konno,
Tsutomu Toki,
Satoru Tandai,
Gang Xu, Runan Wang,
Kiminori Terui,
Shouichi Ohga,
Toshiro Hara,
Asahito Hama,
Seiji Kojima,
Daiichiro Hasegawa,
Yoshiyuki Kosaka,
Ryu Yanagisawa,
Kenichi Koike,
Rie Kanai,
Tsuyoshi Imai,
Teruaki Hongo,
Myoung-Ja Park,
Kanji Sugita,
Etsuro Ito
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ABSTRACT: Diamond-Blackfan anemia is a rare, clinically heterogeneous, congenital red cell aplasia: 40% of patients have congenital abnormalities. Recent studies have shown that in western countries, the disease is associated with heterozygous mutations in the ribosomal protein (RP) genes in about 50% of patients. There have been no studies to determine the incidence of these mutations in Asian patients with Diamond-Blackfan anemia.
We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A. RPS14 was also examined due to its implied involvement in 5q- syndrome.
Mutations in RPS19, RPL5, RPL11 and RPS17 were identified in five, four, two and one of the probands, respectively. In total, 12 (27%) of the Japanese Diamond-Blackfan anemia patients had mutations in ribosomal protein genes. No mutations were detected in RPS14, RPS24 or RPL35A. All patients with RPS19 and RPL5 mutations had physical abnormalities. Remarkably, cleft palate was seen in two patients with RPL5 mutations, and thumb anomalies were seen in six patients with an RPS19 or RPL5 mutation. In contrast, a small-for-date phenotype was seen in five patients without an RPL5 mutation.
We observed a slightly lower frequency of mutations in the ribosomal protein genes in patients with Diamond-Blackfan anemia compared to the frequency reported in western countries. Genotype-phenotype data suggest an association between anomalies and RPS19 mutations, and a negative association between small-for-date phenotype and RPL5 mutations.
Haematologica 04/2010; 95(8):1293-9. · 6.42 Impact Factor
