1989 Fiscal Year Final Research Report Summary
Classification of human hypercholesterolemia by using somatic cell mutants with altered response to low density lipoprotein.
| Project/Area Number |
62870012
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
General medical chemistry
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| Research Institution | Medical College of Oita |
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Principal Investigator |
KUWANO Michihiko Medical College of Oita, Department of Biochemistry Professor, 医学部, 教授 (80037431)
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| Co-Investigator(Kenkyū-buntansha) |
KOHNO Kimitoshi Medical College of Oita, Department of Biochemistry Assistant Professor, 医学部, 助教授 (00153479)
TAKAKI Ryosaburo Medical College of Oita, Professor, 医学部, 教授 (90038620)
ONO Mayumi Medical College of Oita, Department of Biochemistry Assistant, 医学部, 助手 (80128347)
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| Project Period (FY) |
1987 – 1989
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| Keywords | low density lipoprotein / low density lipoprotein receptor / int gene / hypercholesterolemia / metabolic defects of cholesterol / defective O-glycosylation / somatic cell mutants / genetic-biochemistry |
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| Research Abstract |
Familial hypercholesterolemia (FH) are caused by naturally occurring mutation of the low density lipoprotein (LDL) receptor. The repetoire of the naturally occurring mutation is limited. We have developed somatic cell mutants in culture with altered response to LDL, and experimentally induced mutations were successfully introduced into the LDL receptor. Our LDL receptor mutants showed following properties : 1. High cholesterol metabolism and low LDL binding. 2. Maturation of LDL receptor is defective and molecular size of the matured receptor is 5,000 smaller than the wild type. 3. Defective 0-linked sugar chains of LDL receptor. 4.0-linked sugar chains are also defective in the human LDL receptor cDNA-transfected mutants. 5. The defective receptor mutation was expressed recessively and the int gene was mutated in our mutants. 6. Collaboration study with Cummings and Merkle suggested that the dysfunction of LDL receptor was caused by loss of 0-linked sugar chains in LDL-binding or its neighboring domain. 7. The int mutation was supposed to involve in altered Golgi function.
Our study strongly propose that 0-linked sugar chains are indispensable to normal function of LDL receptor. Further study is in progress whether int mutation may cause hypercholesterolemia in human and also isolation of the int gene should be done.
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