2003 Fiscal Year Final Research Report Summary
Clinical and Biological Significance of Granulocyte-Colony-Stimulating-Factor Receptor Truncation Mutations in Severe Congenital Neutropenia.
| Project/Area Number |
14570719
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Yamagata University |
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Principal Investigator |
MITSUI TETSUO Yamagata University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (30270846)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAKAMI TAKAKO Yamagata University, School of Medicine, Assistant, 医学部, 助手 (90312743)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Severe congenital neutropenia / G-CSF receptor / Truncation receptor / G-CSF R Tg mice / Shwachman syndrome / SBDS |
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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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Research Products
(7 results)
