Two partial deletion mutations involving the same Alu sequence within intron 8 of the LDL receptor gene in Korean patients with familial hypercholesterolemia |
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Authors: | Chae Jae Jin Park Young Bae Kim Sung Han Hong Sung Soo Song Gyun Jee Han K H Namkoong Yong Kim Hyo Soo Lee C C |
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Institution: | (1) Department of Molecular Biology, Seoul National University, Seoul, Korea, KR;(2) Department of Biology and SRC for Cell Differentiation, College of Natural Science, Seoul National University, Seoul 151–742, Korea, KR;(3) Tel.: +82-02-880-6691; Fax: +82-02-872-1993,;(4) Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, KR;(5) Department of Biology, Kangnung National University, Kangnung, Korea, KR |
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Abstract: | Twenty-eight unrelated persons heterozygous for familial hypercholesterolemia (FH) were screened to assess the frequency
and nature of major structural rearrangements at the low-density lipoprotein (LDL) receptor gene in Korean FH patients. Genomic
DNA was analyzed by Southern blot hybridization with probes encompassing exons 1–18 of the LDL receptor gene. Two different
deletion mutations (FH29 and FH110) were detected in three FH patients (10.7%). Each of the mutations was characterized by
the use of exon-specific probes and detailed restriction mapping mediated by long-PCR (polymerase chain reaction). Mutation
FH29 was a 3.83-kb deletion extending from intron 6 to intron 8 and FH110 was a 5.71-kb deletion extending from intron 8 to
intron 12. In FH29, the translational reading frame was preserved and the deducible result was a cysteine-rich A and B repeat
truncated protein that might be unable to bind LDL but would continue to bind β-VLDL. FH110 is presumed to be a null allele,
since the deletion shifts the reading frame and results in a truncated protein that terminates in exon 13. Sequence analysis
revealed that both deletions have occurred between two Alu-repetitive sequences that are in the same orientation. This suggested
that in these patients the deletions were caused by an unequal crossing over event following mispairing of two Alu sequences
on different chromatids during meiosis. Moreover, in both deletions, the recombinations were related to an Alu sequence in
intron 8 and the deletion breakpoints are found within a specific sequence, 27 bp in length. This supports the hypothesis
that this region might have some intrinsic instability, and act as one of the important factors in large recombinational rearrangements.
Received: 3 April 1996 / Revised: 19 August 1996 |
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