Yong Namkoong

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

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.

Identification of four novel mutations of the low‐density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia

To obtain insight into the genetic variation of the low‐density lipoprotein (LDL) receptor gene in Korean patients with familial hypercholesterolemia (FH), we used single‐strand conformation polymorphism to screen all 18 exons and a promotor of the LDL receptor gene in 20 unrelated Korean FH patients. Four novel point mutations were detected in 5 FH patients and were characterized by sequence analysis. Of them, one is a nonsense mutation, a Glu→Stop (C AG→T AG) at codon 161, and results in a large deletion. The other three, which were a Ala→Glu (GC G→GĀG) mutation at signal peptide, Cys→Tyr (TG C→TĀC) at codon 210, and Pro→Leu (CT G→CC G) at codon 584, were novel missense mutations, which modified the highly conserved region of the LDL receptor gene. All these mutations were absent in normolipidemic controls and were associated in heterozygote carriers with clinical signs of FH. Identification of these novel mutations provides another example of the molecular heterogeneity of the LDL receptor gene mutations causing FH.

Three novel small deletion mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia

The low‐density lipoprotein (LDL) receptor gene from 80 unrelated Korean patients with familial hypercholesterolemia (FH) was analyzed to screen for small structural rearrangements that could not be detected by Southern blot hybridization. Three different small deletions were detected in exon 11 of 3 FH patients and were characterized by DNA sequence analysis. Of them two mutations are in‐frame 36‐bp (FH 2) and 9‐bp (FH 34) deletions that result in the loss of twelve amino acids (from Met510 to Ile521) and three amino acids (Thr513, Asp514 and Trp515), respectively. Both mutations are located in the third of the five YWTD motifs of the LDL receptor gene. The third mutation (FH 400) is a 2‐bp deletion that shifts the translational reading frame and results in a prematurely terminated receptor protein. The generation of a 36‐bp deletion can be explained by the formation of a hairpin‐loop structure mediated by inverted repeat sequences. On the other hand, the mechanism responsible for the 9‐ and the 2‐bp deletions is probably strand‐slippage mispairing mediated by short direct repeats. All of these three deletions are novel mutations. Each of the three deletions was detected only in a single pedigree out of 80 FH families analyzed.

Haptoglobin polymorphism in Korean patients with cardiovascular diseases

We investigated the relation between hepatoglobin (Hp) polymorphism and plasma lipid levels in 913 Korean subjects. The distribution of Hp phenotypes did not show any significant differences between the healthy controls and the patients with cardiovascular disease. In the control group, however, the subgroup of > or = 50-year-olds had a significantly higher Hp*1 allele frequency than the subgroup <50 years (p < 0.005). This was not seen in the patient group. Hp phenotypes were associated with levels of high-density lipoprotein cholesterol in the hypertensive group. The results indicate that Hp polymorphism, at least in the Korean population, does not predispose to the occurrence of cardiovascular diseases.

Allelic Frequencies of Six (CA)n Microsatellite Markers of the Dystrophin Gene in the Korean Population

Using the polymerase chain reaction, we examined the allele frequencies and heterozygosities of six (CA)n markers of the dystrophin gene in Koreans. Allele frequencies of these markers were different from those reported for Caucasians. The heterozygosity values for these markers range from 29 to 86%. With the exception of the STR50 marker, these values were lower than those of Caucasians. However, all markers except for the 3′CA marker showed PIC values over 0.5, suggesting a high degree of polymorphism. Therefore, this study will be useful in linkage analysis for Duchenne and Becker muscular dystrophy families in the Korean population.

Ethnic differences in allelic frequencies of two (CA)n microsatellite markers located on chromosome 5q

The characteristics of allelic polymorphisms of the two (CA)n microsatellite (p599 and λ599) markers spanning the long arm of chromosome 5 were studied in 52 DNA samples from unrelated inhabitants of Seoul (Korea) by using the polymerase chain reaction (PCR) to investigate differences in allele frequencies between Korean and Caucasian populations. The 6 alleles were observed for p599 (CA)n with a polymorphism informative content (PIC) value of 0.71 and 9 alleles for λ599 (CA)n with a PIC value of 0.82. The observed heterozygote frequencies of the loci were estimated to 0.730 and 0.846, respectively. Several allele frequencies of two loci showed significant differences between Korean and Caucasian populations. Genotype data from the two loci were consistent with the Hardy‐Weinberg equilibrium by χ2 test. Linkage disequilibrium between p599 (CA)n and λ599 (CA)n loci was observed in χ 2 test between the observed and expected frequency of allelic association. The probability of matching calculated at each loc...