Mutation in LDL Receptor: Alu-Alu Recombination Deletes Exons Encoding Transmembrane and Cytoplasmic Domains
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Discussion
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Implication
Molecular analysis reveals an Alu-Alu recombination deleting LDL receptor domains in familial hypercholesterolemia cells, highlighting the genetic basis of defective receptor internalization.
Key Points
- To determine the molecular genetic mutation causing an internalization-defective LDL receptor in cultured fibroblasts from a patient with familial hypercholesterolemia.
- Cloned the genomic DNA segment encoding the truncated portion of the LDL receptor from FH 274 patient fibroblasts into bacteriophage lambda.
- Sequenced and compared the normal and mutant LDL receptor genes and evaluated receptor cellular distribution and binding activity.
- Identified a 5-kilobase deletion eliminating exons that encode the membrane-spanning region and carboxyl-terminal cytoplasmic domain, producing a receptor 10,000 daltons smaller than normal.
- Mapped the deletion breakpoint to an intrastrand recombination event between two oppositely oriented repetitive Alu sequences.
- Demonstrated that truncated receptors are mostly secreted into culture medium, while the remaining surface-bound receptors bind LDL but fail to cluster in coated pits.
Cite This Study
Lehrman et al. (1985) studied this question.