| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
The granulocyte-colony-stimulating factor receptor (G-CSFR) is a member of the cytokine receptor superfamily. Some truncation-receptor-type mutations were identified as an etiological gene for severe congenital neutropenia (SCN) before, and approximately 20% of cases reported to have these mutations in western countries. We studied 17 Japanese SCN patients, and found there was only a case that showed truncation mutation. This mutation was found in mRNA from a blood cell specimen with leukemic blast. Interestingly, genome DNA from hair and nail of this patient had normal gene for G-CSFR. This fact showed the truncation mutation is a secondary abnormality rather than etiological mutation for SCN. We found a point mutation and a polymorphism from our cohort except truncation mutations.
Bone marrow derived cells-semi-solid culture from G-CSFR Tg mice that we made before, showed hyper responsiveness in the stimulation of G-CSF. In vivo high dose administration of G-CSF in this mice resulted
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in pancytopenia. However, the administration of clinical ordinary dose for 250 days, both myelodysplastic syndrome/acute myeloid leukemia was not appeared.
Shwachman-Diamond syndrome (SDS) is a disorder characterized by pancreatic exocrine insufficiency, congenital neutropenia and skeletal changes. Recently, the cause of SDS was identified as the mutation of Shwachman-Bodian-Diamond syndrome gene (SBDS). We analyzed 9 Japanese patients including one sibling and detected the three different mutations in SBDS from 7 patients : a T changed to C that causes donor splice site disruption resulted in deletion of 8bp at the end of the exon 2 (258+2 T>C), a TA→CT dinucleotide change that introduces an in-frame stop codon (183-184 TA>CT) and a 4-bp deletion that causes premature termination by frameshift (292-295 delAAAG). Of the 7 patients with SBDS mutations, persistent hematologic abnormalities and skeletal changes were not observed in 3 and 2 patients, respectively. Notably, these variations were observed even among the patients with identical genotype of a sibling. Less
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