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Biomedical subjects

U K Kim

Publications and source records attributed to U K Kim.

14 recordsLinked to original sources
PubMed2005

Genetics of individual differences in bitter taste perception: lessons from the PTC gene.

The ability or inability to taste the compound phenylthiocarbamide (PTC) is a classic inherited trait in humans and has been the subject of genetic and anthropological studies for over 70 years. This trait has also been shown to correlate with a number of dietary preferences and thus may have important implications for human health. The recent identification of the gene that underlies this phenotype has produced several surprising findings. This gene is a member of the T2R family of bitter taste receptor genes. It exists in seven different allelic forms, although only two of these, designated the major taster and major non-taster forms, exist at high frequency outside sub-Saharan Africa. The non-taster allele resides on a small chromosomal region identical by descent, indicating that non-tasters are descended from an ancient founder individual, and consistent with an origin of the non-taster allele preceding the emergence of modern humans out of Africa. The two major forms differ from each other at three amino acid positions, and both alleles have been maintained at high frequency by balancing natural selection, suggesting that the non-taster allele serves some function. We hypothesize that this function is to serve as a receptor for another, as yet unidentified toxic bitter substance. At least some of the remaining five haplotypes appear to confer intermediate sensitivity to PTC, suggesting future detailed studies of the relationships between receptor structure and taste function.

Alleles↗
PubMed2002

Three novel mutations of the PKD1 gene in Korean patients with autosomal dominant polycystic kidney disease.

Mutations at the PKD1 locus account for 85% of cases of the common genetic disorder called autosomal dominant polycystic kidney disease (ADPKD). Screening for mutations of the PKD1 gene is complicated by the genomic structure of the 5'-duplicated region encoding 75% of the gene. To date, more than 90 mutations of the PKD1 gene have been reported in the European and American populations, and relatively little information is available concerning the pattern of mutations present in the Asian populations. We looked for mutations of the PKD1 gene in 51 unrelated Korean ADPKD patients, using polymerase chain reaction (PCR) with primer pairs located in the 3' single-copy region of the PKD1 gene and by single-strand conformation polymorphism (SSCP) analysis. We found three novel mutations, a G to A substitution at nucleotide 11012 (G3601S), a C to A substitution at nucleotide 11312 (Q3701X), and a C to T substitution at nucleotide 12971 (P4254S), and a single polymorphism involving a G to C substitution at nucleotide 11470 (L3753L). These mutations were not found in control individuals, and no other mutations in the 3' single-copy region of the PKD1 gene of patients with these mutations were observed. In particular, P4254S segregated with the disease phenotype. The clinical data of affected individuals from this study, and of previously reported Korean PKD1 mutations, showed that patients with frameshift or nonsense mutations were more prone to develop end-stage renal failure than those with missense mutations. Our findings indicate that many different PKD1 mutations are likely to be responsible for ADPKD in the Korean population, as in the Western population.

Female↗
PubMed2001

Genetic heterogeneity in Korean families with autosomal-dominant polycystic kidney disease (ADPKD): the first Asian report.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in adults, and the prevalence of this disease within the chronic haemodialysis patient population is known to be approximately 2% in Korea. So far, three genetic locus have been identified as being responsible for ADPKD, and approximately 85% of the cases in Western countries are related to the PKD1 gene. However, little information is available concerning the pattern of linkage analysis in Asian populations. METHODS: 48 families with hereditary renal cysts were recruited by consent and their molecular genetic characteristics were studied. Linkage analysis was done with microsatellite markers (PKD1: SM7, UT581, AC2.5, KG8, D16S418; PKD2: D4S423, D4S1534, D4S1542, D4S1544, D4S2460). Genomic DNA polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) gel run were performed, and the resultant allele patterns were compared with sonographic findings. RESULTS: The results of this study showed that the ratio PKD1:PKD2 was 31:8, and that the PKD2 families exhibited a tendency toward a milder renal prognosis than the PKD1 families. CONCLUSION: We confirmed the applicability of linkage analysis for ADPKD in the Korean population, and our data confirmed a similar incidence of PKD1 (79%) and PKD2 (21%) in Korean patients as in the Western population.

Adolescent↗
PubMed2001

Identification of mutations including de novo mutations in Korean patients with hypokalaemic periodic paralysis.

BACKGROUND: Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant disorder involving the abnormal function of ion channels and it is characterized by paralysis attacks of varying severity, accompanied by a fall in blood potassium levels. Linkage analysis showed that the candidate locus responsible for hypoPP was localized to chromosome 1q31-32, and this locus encoded the muscle dihydropyridine-sensitive calcium channel alpha(1)-subunit (CACNA1S). So far, three different mutations in CACNA1S gene have been identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly in Caucasian patients. However, there are few reports about the mutations of CACNA1S gene in other races. METHODS: In this study, four Korean families with five hypoPP patients were screened for mutations of CACNA1S gene with polymerase chain reaction-based restriction analysis and single-strand conformation polymorphism analysis. To determine the mode of inheritance, haplotype analysis was done with three microsatellite markers (D1S1726, CACNL1A3, and D1S1723). RESULTS: Arg528His mutation was detected in three families, and one family had no known mutations. Moreover, for the first time, we detected de novo Arg528His mutations in two out of three families with hypoPP. Haplotype analysis using three microsatellite markers (D1S1726, CACNL1A3, and D1S1723) suggested the occurrence of de novo Arg528His mutations in two of the three families with Arg528His mutation. CONCLUSIONS: Arg528His mutations of CACNA1S, including de novo Arg528His mutations, were found in Korean patients with hypoPP. These results imply that de novo mutation, in addition to non-penetrance, is one of the genetic mechanisms that can explain the previous clinical observation that hypoPP occurs sporadically without family history.

Adolescent↗
PubMed2001

Polymorphic DNA haplotypes at the human low-density lipoprotein receptor gene locus in Koreans.

Many low-density lipoprotein (LDL) receptor mutations have been identified and characterized, demonstrating a high degree of allelic heterogeneity at this locus. The ability to identify mutant LDL-receptor genes for prenatal diagnosis of familial hypercholesterolemia (FH) or to study the role of the LDL-receptor gene in polygenic hypercholesterolemia requires the use of closely linked restriction fragment lenghth polymorphisms (RFLPs). In the present study nine different RFLPs (TaqI, StuI, HincII, BstEII, AvaII, PvuII, MspIA, MspIB, and NcoI) and a sequence variation at Arg450 were used to clarify the characteristics of the LDL-receptor gene in Koreans. A total of 978 LDL-receptor alleles from 244 members of 43 different pedigrees (15 normal and 28 FH pedigrees) and 245 individuals (187 normal and 58 FH) were analyzed. Frequencies of these polymorphisms did not differ significantly between controls and FH patients. Individually, seven sites--TaqI, BstEII, AvaII, MspIA, MspIB, NcoI and Arg450--had heterozygosity indices ranging from 0.3610 to 0.4601, whereas the PvuII site displayed low levels of polymorphism and StuI was monomorphic. Haplotypes were constructed for 215 individuals of 13 normal and 24 FH pedigrees using the nine polymorphisms. Of 512 (= 2(9)) possible combinations for the nine polymorphic sites, 39 unique haplotypes were detected. The frequency distribution of individual haplotypes ranged from 1/155 (0.65%) to 40/155 (25.8%). The four most common haplotypes accounted for 59.4% of those sampled. Statistical analysis of the haplotypes indicated marked linkage disequilibrium for these 10 sites and throughout the region containing the LDL-receptor gene. Owing to the high degree of linkage disequilibrium over the entire locus, not all RFLPs were informative. We rank each RFLP according to its informativeness and present a strategy for the optimal selection of RFLPs for pedigree analysis.

Genetics, Population↗
PubMed2000

Analysis of mitochondrial DNA deletions in four chambers of failing human heart: hemodynamic stress, age, and disease are important factors.

Mitochondrial DNA (mtDNA) mutations are not only responsible for organ dysfunction due to inefficient energy production but also indicators of metabolic and functional stresses in the organ. To analyze the significance of deletion mutation in human myocardium, we screened the presence of two common deletions (7.4 kb from 8637-16084 nt, 5.0 kb from 8470-13477 nt) in four chambers using long-PCR, and using serial-dilution PCR, measured the amount of deleted mtDNA in normal heart (NL) of brain-dead victims of road accidents (n = 9, age = 10-59) and failing hearts (CHF) of patients who underwent heart transplantation (n = 24, age = 17-63). Frequency of both deletions was higher in ventricles (Vt) than in atria (At) (Vt:At = 25/33:12/33 for 7.4 kb, 19/33:6/33 for 5 kb) (p < 0.05), whereas it was the same in the right and left chambers. In ventricles, both deletions were more frequent among older persons (> 35 yrs) than in younger persons (< or = 35 yrs) (older:younger = 16/20:9/13 for 7.4 kb, 15/20:4/13 for 5 kb) (p < 0.05). In ventricles of failing heart, the 5-kb deletion was more frequent than in those of normal heart (CHF:NL = 17/24:2/9) (p < 0.05), whereas the 7.4-kb deletion was frequent both in failing and normal hearts (CHF:NL = 19/24:6/9). The association of mutation with aging or disease process observed in ventricles was not found in the atria. Although the amount of mutant mtDNA in the left ventricle tended to increase according to a disease process, it was small, at most 1.56% or 0.012% of total mtDNA for a 7.4- or 5-kb deletion, respectively. No deletion was found, however, in lymphocytes from any patient who underwent transplantation. In conclusion, deletion mutation of mtDNA is frequently, but in a small amount, found in the ventricle of older failing heart than in the atrium of younger normal heart. This suggests that hemodynamic stress, age, and disease are factors to induce mtDNA mutation that represents the indicator of stresses on the heart and might turn into a contributor of progressive heart failure under extreme conditions.

Adolescent↗
PubMed2000

Novel mutations of the PKD1 gene in Korean patients with autosomal dominant polycystic kidney disease.

The gene for the most common form of autosomal dominant polycystic kidney disease (ADPKD), PKD1, has recently been characterized and shown to encode an integral membrane protein, polycystin-1, which is involved in cell-cell and cell-matrix interactions. Until now, approximately 30 mutations of the 3' single copy region of the PKD1 gene have been reported in European and American populations. However, there is no report of mutations in Asian populations. Using the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis, 91 Korean patients with ADPKD were screened for mutation in the 3' single copy region of the PKD1 gene. As a result, we have identified and characterized six mutations: three frameshift mutations (11548del8bp, 11674insG and 12722delT), a nonsense mutation (Q4010X), and two missense mutations (R3752W and D3814N). Five mutations except for Q4010X are reported here for the first time. Our findings also indicate that many different mutations are likely to be responsible for ADPKD in the Korean population. The detection of additional disease-causing PKD1 mutations will help in identifying the location of the important functional regions of polycystin-1 and help us to better understand the pathophysiology of ADPKD.

Frameshift Mutation↗
PubMed2000

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 (CAG-->TAG) at codon 161, and results in a large deletion. The other three, which were a Ala-->Glu (GCG-->GAG) mutation at signal peptide, Cys-->Tyr (TGC-->TAC) at codon 210, and Pro-->Leu (CTG-->CCG) 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.

Adult↗
PubMed2000

Association of the ACE gene polymorphism with the progression of autosomal dominant polycystic kidney disease.

Renin-angiotensin system is considered important in the genesis of hypertension and development of end-stage renal disease (ESRD) in autosomal dominant polycystic kidney disease (ADPKD). The angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with susceptibility to the development of some renal diseases. We investigated the association of ACE gene polymorphism with the progression to hypertension and ESRD in 108 patients with ADPKD. The ACE I/D polymorphism was amplified with the flanking primers by polymerase chain reaction. In patients genotyped for ACE gene polymorphism, the frequencies of DD (15%), ID (51%) and II (34%) genotypes were similar to those of the general population. Of the 108 patients, 64 (59%) developed hypertension and 24 (22%) reached ESRD at the time of study. The prevalence of hypertension was not significantly different among the three genotypes. The mean renal survival time was 53-6 yr in II genotype, 55+/-10 yr in ID genotype and 52+/-9 yr in DD genotype which was not significantly different among them. Cumulative renal survival was not significantly different either. There was no association of ACE gene polymorphism with the prevalence of hypertension and renal survival in ADPKD. We suggest that ACE I/D polymorphism is not an important modifying gene in the progression of ADPKD.

Adult↗
PubMed1999

Polymorphisms in the human autosomal dominant polycystic kidney disease 2 (PKD2) gene.

Three polymorphisms of the PKD2 (MIM 173910) gene in patients with autosomal dominant polycystic kidney disease are reported: (1) a substitution from ATT (isoleucine) to GTT (valine) at codon 452; (2) a substitution from CGG (arginine) to CAG (glutamine) at codon 848; and (3) a substitution from G to A in intron 4 of the gene. The minor allelic frequencies of codon 452 and intron 4 in the Korean population were estimated to be 0.03 and 0.32, respectively. Although the codon 848 substitution was not observed in 45 unrelated healthy Korean people, the substitution did not cosegregate with the disease phenotype, suggesting that this was a rare, non-deleterious alteration.

Alleles↗
PubMed1999

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.

Adult↗
PubMed1999

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.

Alleles↗
PubMed1999

Long-distance PCR-based screening for large rearrangements of the LDL receptor gene in Korean patients with familial hypercholesterolemia.

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.

Base Sequence↗