Classification of human hypercholesterolemia by using somatic cell mutants with altered response to low density lipoprotein.

家族性高胆固醇血症（FH）是由低密度脂蛋白（LDL）受体的自然突变引起的。自然发生的突变的重复序列是有限的。我们已经在培养中培养出对LDL反应改变的体细胞突变体，并通过实验成功地将诱导突变引入LDL受体。我们的LDL受体突变体表现出以下特性：高胆固醇代谢和低LDL结合。2. LDL受体成熟有缺陷，成熟受体的分子大小比野生型小5000。3. LDL受体0链糖链缺陷。在人类LDL受体cdna转染突变体中，4.0链糖链也存在缺陷。5. 在我们的突变体中，缺陷受体突变隐性表达，int基因突变。6. 与Cummings和Merkle的合作研究认为LDL受体功能障碍是由于LDL结合或其邻近结构域的0链糖链缺失引起的。7. int突变被认为与高尔基体功能的改变有关。我们的研究有力地表明，0链糖对于LDL受体的正常功能是不可或缺的。int突变是否会引起人类高胆固醇血症的进一步研究正在进行中，还需要进行int基因的分离。

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.