Mutation in LDL Receptor: Alu-Alu Recombination Deletes Exons Encoding Transmembrane and Cytoplasmic Domains
10.1126/science.3155573
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

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.

Bibliography

Lehrman, M. A., Schneider, W. J., Südhof, T. C., Brown, M. S., Goldstein, J. L., & Russell, D. W. (1985). Mutation in LDL Receptor: Alu-Alu Recombination Deletes Exons Encoding Transmembrane and Cytoplasmic Domains. Science, 227(4683), 140–146.

Authors 6
  1. Mark A. Lehrman (first)
  2. Wolfgang J. Schneider (additional)
  3. Thomas C. Südhof (additional)
  4. Michael S. Brown (additional)
  5. Joseph L. Goldstein (additional)
  6. David W. Russell (additional)
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Dates
Type When
Created 18 years, 11 months ago (Oct. 5, 2006, 3:42 p.m.)
Deposited 1 year, 7 months ago (Jan. 13, 2024, 4:49 p.m.)
Indexed 1 day, 9 hours ago (Sept. 4, 2025, 9:39 a.m.)
Issued 40 years, 7 months ago (Jan. 11, 1985)
Published 40 years, 7 months ago (Jan. 11, 1985)
Published Print 40 years, 7 months ago (Jan. 11, 1985)
Funders 0

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@article{Lehrman_1985, title={Mutation in LDL Receptor: Alu-Alu Recombination Deletes Exons Encoding Transmembrane and Cytoplasmic Domains}, volume={227}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.3155573}, DOI={10.1126/science.3155573}, number={4683}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Lehrman, Mark A. and Schneider, Wolfgang J. and Südhof, Thomas C. and Brown, Michael S. and Goldstein, Joseph L. and Russell, David W.}, year={1985}, month=jan, pages={140–146} }