Two partial deletion mutations involving the same Alu sequence within intron 8 of the LDL receptor gene in Korean patients with familial hypercholesterolemia

被引:27
作者
Chae, JJ
Park, YB
Kim, SH
Hong, SS
Song, GJ
Han, KH
Namkoong, Y
Kim, HS
Lee, CC
机构
[1] SEOUL NATL UNIV,COLL NAT SCI,DEPT BIOL,SEOUL 151742,SOUTH KOREA
[2] SEOUL NATL UNIV,COLL NAT SCI,SRC CELL DIFFERENTIAT,SEOUL 151742,SOUTH KOREA
[3] SEOUL NATL UNIV,DEPT MOL BIOL,SEOUL,SOUTH KOREA
[4] SEOUL NATL UNIV HOSP,DEPT INTERNAL MED,SEOUL 110744,SOUTH KOREA
[5] KANGNUNG NATL UNIV,DEPT BIOL,KANGNUNG,SOUTH KOREA
关键词
D O I
10.1007/s004390050331
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 beta-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.
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页码:155 / 163
页数:9
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