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Clinical Chemistry 45: 1424-1430, 1999;
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(Clinical Chemistry. 1999;45:1424-1430.)
© 1999 American Association for Clinical Chemistry, Inc.

Articles

Long-Distance PCR-based Screening for Large Rearrangements of the LDL Receptor Gene in Korean Patients with Familial Hypercholesterolemia

Sung Han Kim1, Ji Hyun Bae2, Jae Jin Chae2, Un Kyung Kim2, Seong-Joon Choe3, Yong Namkoong4, Hyo-Soo Kim3, Young-Bae Park3 and Chung Choo Lee1,a

1 Department of Biology and SRC for Cell Differentiation, and
2 Department of Molecular Biology, Seoul National University, Seoul 151-742, Korea.

3 Department of Internal Medicine, Seoul National University Hospital, Seoul 110-799, Korea.

4 Department of Biology, Kangnung National University, Kangnung 210-702, Korea.
a Address correspondence to this author at: Department of Biology, College of Natural Science, Seoul National University, Seoul 151-742, Korea. Fax 82-02-872-1993; e-mail chunglee{at}plaza.snu.ac.kr

Background: The LDL receptor is a cell-surface protein that regulates plasma cholesterol by specific uptake of LDL particles from the blood circulation. Familial hypercholesterolemia (FH) results from defective catabolism of LDL, which is caused by mutations in the LDL-receptor gene.

Methods: For the rapid and reliable detection of large rearrangements in the LDL-receptor gene, we established a screening method based on long-distance PCR as an alternative to Southern-blot hybridization. Using long-distance PCR, 45 unrelated Korean subjects heterozygous for FH were screened to assess the frequency and nature of major structural rearrangements in the LDL-receptor gene.

Results: Two different deletion mutations, FH6 (same type as FH3 and FH311) and FH 32, were detected in four families by long-distance PCR. Detailed restriction mapping and sequence analysis showed that FH6 was a 5.71-kb deletion extending from intron 8 to intron 12 and that FH32 was a 2-kb deletion extending from intron 6 to intron 7. Sequence analysis for the breakpoints of all deletions detected in Korean FH patients showed that only the left arms of the Alu repetitive sequences were involved in the deletion event.

Conclusions: The screening method based on long-distance PCR provides a powerful strategy for the detection of large rearrangements in the LDL-receptor gene and is a rapid and reliable screening alternative to Southern-blot hybridization.






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Copyright © 1999 by the American Association for Clinical Chemistry.