1998 Fiscal Year Final Research Report Summary
Molecular basis of late onset ornithine transcarbamylase deficiency in male
| Project/Area Number |
08671192
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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 |
内分泌・代謝学
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| Research Institution | Kurume University |
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Principal Investigator |
NISHIYORI Atsushi Kurume University School of Medicine, Assistant Professor, 医学部, 助手 (30218226)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHINO Makoto Kurume University School of Medicine, Professor, 医学部, 教授 (40080569)
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| Project Period (FY) |
1996 – 1998
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| Keywords | ornithine transcarbamylase deficiency / late onset / expression analysis |
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| Research Abstract |
We had reported a cluster of male ornithine transcarbamylase deficiency (OTC) patients with onset from late adolescence to the presenile period. In this study, we discovered three patients who have R4OH mutation. We detected R4OH mutation in liver specimens from one of the patients with RFLP, but in fibroblast and skin specimens the RFLP showed almost normal. This result indicated that the R4OH mutation in the patient may be somatic mutation. The R4OH mutation has been discovered in different ethnic groups. This mutation may arise as a result of a recurrent mutation because the mutation involves a CpG island.
We have showed that posttranslational mechanisms related late onset omithine transcarbamylase deficiency patients bearing R4OH or Y55D mutations. In this study, expression analysis using Cos 1 cells indicated that the OTC activities of cells transfected with the plasmid only, and the plasmid containing wild type cDNA were 23.5 (nmol/min/ml) and 1955*140 (n=3) respectively. On the other hand OTC activities with R4OH mutant cDNA, and Y55D cDNA were 670*130 (n=3) and 627*124 (n=3) respectively. The activities of R4OH mutant OTC and Y55D mutant OTC, as normalized for beta-galactosidase activity were 28% and 26% of the normal OTC activity respectively. When the cell lysates were subjected to five cycles of freezing and thawing, the activities of the wild type OTC and Y55D mutant OTC did not change, whereas the activity of the R4OH mutant OTC decreased to 6% of wild type that before treatment. These results indicated that the R4OH mutant OTC was physically unstable and was degraded more rapidly than the wild type enzyme. Thus, the R4OH OTC activity may be depressed to an incompatible level once a metabolic burden that would facilitate inactivation and degradation of the mutant enzyme is applied.
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[Publications] Ichiro Matsuda, Toshinobu Matsuura, Atsushi Nishiyori, Satoru Komaki, Ryuuji Hoshiide, Tadashi Matsumoto, Mitsuhiko Funakoshi, Kohoji Kiwaki, Fumio Endo, Akira Hata, Mitsunobu Shimadzu and Makoto Yoshino: "Phenotypic variability in male patients carring the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult." Med Genet. Vol.33. 645-648 (1996)
Description
「研究成果報告書概要(欧文)」より
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