Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

Association between a polymorphism in the lymphotoxin-a promoter region and migraine.

OBJECTIVE: The aim of this study was to determine whether polymorphisms in the lymphotoxin (LTA)-tumor necrosis factor (TNF) region are associated with the risk of migraine. BACKGROUND: Previous studies concerning the role of TNFalpha in migraine have provided conflicting results. It has been reported that LTA could be a susceptibility gene in migraine. It is possible that the TNFalpha polymorphism associated with migraine is in linkage disequilibrium with other functional polymorphisms that influence migraine risk. Moreover, there are significant differences among the allele frequencies of TNF gene variants among populations from different ethnic groups. METHODS: In a case-control study, including 439 migraine patients and 382 controls, we examined the association between 15 single nucleotide polymorphisms in the coding and promoter regions of LTA and TNFalpha genes, which are located within the 22 kb around TNF and the risk of migraine. We performed a chromatin immunoprecipitation (ChIP) assay and an electrophoretic mobility shift assay (EMSA) to identify differential protein-DNA binding of LTA-294. RESULTS: Homozygosity for the LTA-294C allele was significantly associated with an increased risk of migraine compared with CT/TT carriers (corrected P= .005, odds ratio [OR]= 1.7, 95% confidence interval [CI] 1.3-2.3). Haplotype TGAAC was found to be significantly associated with a protective effect against migraine (P= .0005, Bonferroni corrected P= .003, OR = 0.7, 95% CI 0.5-0.8). There was no differential protein-DNA binding pattern in both EMSA and ChIP assays. CONCLUSIONS: We found that the LTA haplotypes were associated with migraine among Koreans and that the best marker for this is the LTA-294 T/C polymorphism. Our results indicate that these associations should be defined in the context of the involvement of other genetically linked region, such as human leukocyte antigen (HLA) loci.

Distinct linkage disequilibrium (LD) runs of single nucleotide polymorphisms and microsatellite markers; implications for use of mixed marker haplotypes in LD-based mapping.

It has been suggested that the haplotypic relationship between microsatellite markers and single nucleotide polymorphisms (SNPs) is of considerable importance, as microsatellite markers can potentially be incorporated into haplotypes containing SNPs to increase marker density across a region of interest. However, SNPs and microsatellite markers have different mutation rates and durations, and it is conceivable that the linkage disequilibrium (LD) patterns between the genetic markers may considerably differ. We assessed the LD patterns using 1,661 SNPs and 65 microsatellite markers along chromosome 22 and investigated whether common patterns of LD between the two genetic markers are deduced from the results. The results demonstrated that the patterns of LD among microsatellite markers varied considerably and the LD runs of SNPs and microsatellite markers showed distinct patterns. Microsatellite markers have a much higher mutation rate and the evolution of microsatellite markers is a more complex process which has distinct mutation properties from those of SNPs. We consider that these might contribute to the different LD patterns between the two genetic markers. Therefore, it would seem inadvisable to make assumptions about persistence of LD across even a relatively small genetic distance among microsatellite markers and to construct mixed marker haplotypes/LD maps employing microsatellite markers.

Sequence-based CYP2D6 genotyping in the Korean population.

For clinical application of pharmacogenetic tests, quantitative prediction of enzyme activity based on accurate determination of genotype is essential. There has been limited information available on the genetic polymorphism of CYP2D6 in the Korean population. In this study, CYP2D6 genotypes were assessed in 400 Korean subjects. Twenty-eight different CYP2D6 alleles and 35 genotypes were detected. On the basis of the genotype determined, the frequency of poor metabolizers and ultrarapid metabolizers were 0.22% and 1.25%, respectively. The CYP2D6 activity expected in regard to different allele combinations varies widely within the extensive and intermediate metabolizer groups. The frequencies of CYP2D6*10 and CYP2D6*5 were 45.00% and 6.13%, respectively. CYP2D6*10xN was found in 4 out of 9 cases with a CYP2D6 duplication. Fifteen heterozygotes for *41 were noted. In addition, the authors measured plasma concentrations of 16 healthy volunteers after administration of nortriptyline and identified the impact of the CYP2D6 genotype on nortriptyline metabolism. This is the first large-scale study to examine the genetic polymorphism of CYP2D6 using sequence-based genotyping in an Asian population. Our results further the understanding of CYP2D6 pharmacogenetics and could be helpful for future clinical studies in the Asian population.

Novel interleukin 1beta polymorphism increased the risk of gastric cancer in a Korean population.

BACKGROUND: Polymorphisms in the gene for interleukin 1beta (IL-1B) have been found to increase the risks of gastric cancer and its precursors in response to Helicobacter pylori infection in white populations. however, there has been no independent confirmation of the role of IL-1B markers in gastric cancer patients from Asian populations. Moreover, there have been conflicting data regarding the effect of IL-1B-511/-31 on the risk of gastric cancer or its precursors in Asian populations. Therefore, we assessed an additional polymorphism in the promoter region of IL-1B at position-1473 with the IL-1B-511/-31 polymorphisms in a Korean population. METHODS: In a case-control study, including 331 gastric cancer cases and 433 controls, we assessed the association between the three polymorphisms and the risk of gastric cancer. All genotyping was performed in duplicate. To assess the DNA-binding activity of IL-1B-1473 in vitro, we performed an electrophoretic mobility shift assay (EMSA). RESULTS: When cases were divided according to the histologic type of the tumor, a significant difference in genotype frequencies for IL-1B-1473 was observed only between intestinal-type cases and controls (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.0-3.5 and OR 2.1 and 95% CI, 1.1-4.2 in the CG and GG genotypes, respectively). In the cases, there was a deviation from Hardy-Weinberg equilibrium in the IL-1B-511/-31 loci confined to the intestinal type, due to the excess of heterozygotes. The IL-1B-1473G allele showed decreased binding to nuclear extract, indicating a wearker promoter activity on EMSA. CONCLUSIONS: We identified a novel single-nucleotide polymorphism, 1473C-->G, in the IL-1B promoter that was significantly associated with gastric cancer among Koreans. Our results also suggest that the association between IL-1B polymorphism and an increased risk of gastric cancer may depend on the histologic type of gastric cancer.

A novel missense mutation (I344K) in the SPG4gene in a Korean family with autosomal-dominant hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities. Among eight loci linked with autosomal-dominant (AD)-HSP, the SPG4 locus on chromosome 2p22 accounts for about 40% of all patients. Recently, mutations in a new member of the AAA protein family, called spastin, have been identified as responsible for SPG4-linked AD-HSP. Here, we describe a novel missense mutation (c.1031T>A; I344K) in exon 7 of the SPG4 gene identified in a Korean family with typical clinical features of pure AD-HSP. The mutation affects the third amino acid of the highly conserved AAA cassette domain, which is the most fore part of the domain altered by a missense mutation reported so far. Clinical presentations of affected individuals carrying the I344K mutation were not different from those of pure AD-HSP with SPG4 mutations reported previously. However, it is noteworthy that neither urinary dysfunction nor involvement of upper extremities was noticed in this family. To our knowledge, this is the first report of genetically confirmed AD-HSP in Korea.