2003 Fiscal Year Final Research Report Summary
Cloning of the Causative Gene for Type II Cystinuria
| Project/Area Number |
13470330
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Chiba University |
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Principal Investigator |
ITO Haruo Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (20009583)
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| Project Period (FY) |
2001 – 2003
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| Keywords | Cystinuria / Cystinuria gene / R BAT gene / BAT1 gene / Urinary excretion of cystine / Stone recurrence / Order-made medicine / Gene therapy |
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| Research Abstract |
In 1992, the rBAT gene was identified as a causative gene for cystinuria. We discovered 5 new mutations of the rBAT gene in type I cystinuria in 43 patients. In 1999, we identified BAT1 as a causative gene in non-type I cystinuria. The BAT1 protein is an approximately 40-kDa protein that encodes 487 amino acids. In humans, BAT1 mRNA was shown to be present in the renal proximal tubular lumen.
Functional studies suggest that the 2 molecules encoded by the rBAT and BAT1 genes are dimeric membrane proteins on renal tubular luminal membranes that function as cystine transporters. An analysis of the BAT1 gene in 41 patients detected 7 mutations. In 2 patients, there were no mutations of either gene. A high frequency of a P482L (PRO 482 to LEU) missense mutation in the BAT1 gene was detected in 31 of 35 patients (about 90%).
This mutation in the intracytoplasmic C terminus of the BAT protein, specifically 6 amino acids before the stop codon, causes a decrease in cystine absorption. Rather than a change in the structure of the protein itself, there is inhibition or regulatory factor binding. This leads to sorting abnormalities to luminal cell membranes. The P482L mutation has not been reported in genetic analysis in Westerners. This is a "hot spot" mutation for cystinuria in Japanese patients. Correlation of clinical findings with these gene mutations shows that patients with type I cystinuria have a lower incidence of stone recurrence and lower urinary excretion of cystine than those with non-type I cystinuria. Therefore, genetic diagnosis to predict discase severity can be clinically useful not only in preventing stone recurrence in known cases, but also in preventing the onset of disease in asymptomatic carriers.
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Research Products
(20 results)
