MUTATION IN LDL RECEPTOR - ALU-ALU RECOMBINATION DELETES EXONS ENCODING TRANSMEMBRANE AND CYTOPLASMIC DOMAINS
MUTATION IN LDL RECEPTOR - ALU-ALU RECOMBINATION DELETES EXONS ENCODING TRANSMEMBRANE AND CYTOPLASMIC DOMAINS
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DOI：
10.1126/science.3155573
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发表时间：
1985-01-01
期刊：
影响因子：
56.9
通讯作者：
RUSSELL, DW
中科院分区：
文献类型：
--
作者：
LEHRMAN, MA;SCHNEIDER, WJ;RUSSELL, DW
由来自患有内化缺陷型家族性高胆固醇血症（FH 274）的患者的培养的成纤维细胞合成的血浆LDL（低密度脂蛋白）受体的分子大小比正常LDL受体的大小小10，000道尔顿。将编码FH 274受体截短部分的基因片段克隆入λ噬菌体。正常和FH 274基因的核苷酸序列的比较揭示了5-巯基转移酶缺失，其消除了编码受体的跨膜区和羧基末端胞质结构域的外显子。删除似乎是由一种新的两个重复序列的Alu家庭，在相反的方向取向之间的链内重组。截短的受体缺乏跨膜区域和胞质结构域;它们大部分分泌到培养基中，但一小部分仍然粘附在细胞表面。表面粘附受体结合LDL，但它们不能聚集在包被的小凹中，从而解释了内化缺陷的表型。
The molecular size of the plasma LDL (low density lipoprotein) receptor synthesized by cultured fibroblasts from a patient with the internalization-defective form of familial hypercholesterolemia (FH 274) was smaller by 10,000 daltons than the size of the normal LDL receptor. The segment of the gene encoding the truncated portion of the FH 274 receptor was cloned into bacteriophage lambda. Comparison of the nucleotide sequences of the normal and FH 274 genes revealed a 5-kilobase deletion, which eliminated the exons encoding the membrane-spanning region and the carboxyl terminal cytoplasmic domain of the receptor. The deletion appeared to be caused by a novel intrastrand recombination between two repetitive sequences of the Alu family that were oriented in opposite directions. The truncated receptors lack membrane-spanning regions and cytoplasmic domains; they are largely secreted into the culture medium, but a small fraction remains adherent to the cell surface. The surface-adherent receptors bind LDL, but they are unable to cluster in coated pits, thus explaining the internalization-defective phenotype.