Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9
Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9
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DOI：
10.1038/ng1509
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发表时间：
2005-02-01
期刊：
影响因子：
30.8
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
--
作者：
Jonathan, C;Pertsemlidis, A;Hobbs, HH
低密度脂蛋白受体（LDLR）通过从循环中清除低密度脂蛋白（LDL）来预防高胆固醇血症和动脉粥样硬化。编码LDLR1或其配体（APOB）的基因发生突变会导致严重的高胆固醇血症。编码分泌途径中一种丝氨酸蛋白酶的PCSK9发生错义突变也会导致高胆固醇血症。这些突变可能是功能获得性突变，因为在小鼠肝脏中过表达PCSK9会通过减少LDLR数量而导致高胆固醇血症。为了测试PCSK9的功能缺失性突变是否有相反的作用，我们对128名低密度脂蛋白血浆水平较低的受试者（50%为非裔美国人）的PCSK9编码区进行了测序，发现了两个无义突变（Y142X和C679X）。这些突变在非裔美国人中很常见（合并频率为2%），但在欧裔美国人中很罕见（
The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR1 or its ligand (APOB)(2) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway(3), also cause hypercholesterolemia(4). These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia(5-7) by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (