| Project/Area Number |
16591028
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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 | National University Corporation Tottori University |
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Principal Investigator |
KANZAKI Susumu Tottori University, Faculty of Medicie, Professor, 医学部, 教授 (90224873)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Ikuo Tottori University, Faculty of Medicie, Associate Professor, 医学部, 助教授 (50252846)
NAGAISHI Jun-ichi Tottori University, University Hospital, Assistant Professor, 医学部附属病院, 助手 (90346354)
HANAKI Keiichi Tottori University, Faculty of Medicie, Professor, 医学部, 教授 (20238041)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | insulin-like growth factor / IGF-I / IUGR / IGF-I receptor / insulin receptor / IUGR short stature / インスリン様成長因子受容体 |
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| Research Abstract |
We hypothesized that mutations of insulin-like growth factor (IGF) receptor type 1 (IGF-IR) gene might predispose to short stature and associated with intrauterine growth retardation (IUGR).
Until now we have analyzed the nucleotide sequences of IGF-IR gene in 28 patients with IUGR short stature. Among them we found two patients with IGF-IR gene mutation ; a heterozygous mutation (R709Q) at the cleavage site of IGF-IR and a heterozygous missense mutation at a subunit of IGF-IR (R431L).
A heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-year-old Japanese girl and her mother who also had IUGR short stature. Fibroblasts from the patient contained more unprocessed IGF-IR proreceptor protein and less mature β subunit protein compared to normal fibroblasts. These findings strongly suggest that this mutation lead to failure of processing from IGF-IR proreceptor to mature IGF-IR, and caused short stature and IUGR.
A heterozygous missense mutation at a subunit of IGF-IR (R431L) mutation was identified in a 4-year-old Japanese girl with IUGR short stature and her mother who also had IUGR short stature. She was treated with growth hormone (GH) according to a clinical trial (0.25mg/kg/week), and her height has not improved significantly (from - 3.0 SD to -2.8 SD during 9 months) despite of GH therapy. R432 residue corresponds to L2 domain that is believed to be important for ligand binding. Accordingly, the mutation might cause decreased IGF-I binding, and IUGR short stature. In vitro studies using transfected cells with our IGF-IR mutation are warranted to clarify the exact mechanism of IGF-IR dysfunction.
It is commonly believed that IGF-IR mutations are uncommon causes of IUGR short stature. However, our finding suggests that the actual prevalence of IGF-IR mutations in IUGR short stature might be considerably higher than previously thought.
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