Role of the TAS2R38 Bitter Taste Receptor Gene Single Nucleotide Polymorphism in Patients With Taste Disorders / 대한이비인후과학회지

Background and Objectives@#Several studies have shown that three single nucleotide polymorphisms (SNPs) in the TAS2R38 gene demonstrate a strong association with the ability to sense the bitter taste of phenylthiocarbamide (PTC) in. We have previously reported about TAS2R38 genotypes in normal volunteers. The aim of this study was to investigate the role TAS2R38 gene plays in taste disorder by examining SNPs in the TAS2R38 gene in taste disorder patients.Subjects and Method Ninety-four patients with taste dysfunction from multiple etiologies were enrolled. The genotypes were defined by identifying SNPs on the TAS2R38 gene. The proportion of different TAS2R38 genotypes in the group was compared with that in the normal volunteers of our previous study. The whole mouth taste threshold tests were performed and the thresholds were compared among the three different genotypic groups. @*Results@#The proportion of each diplotype in taste disorder patients were as follows: PAV/ PAV 36.2% (34/94), PAV/AVI 34.0% (32/94), and AVI/AVI 29.8% (28/94). The proportion of AVI/AVI type was higher in the group than in the normal volunteers (p=0.031). The detection and recognition thresholds of all four basic tastes were increased in the order of PAV/PAV, PAV/AVI, and AVI/AVI genotypes. @*Conclusion@#The proportion of AVI/AVI homozygous was significantly higher in taste disorder patients than in the normal volunteers. Our findings suggest that the genotypes of TAS2R38 may represent one of the risk factors responsible for the development of taste disorders.

A Novel Frameshift Mutation of SLC26A4 in a Korean Family With Nonsyndromic Hearing Loss and Enlarged Vestibular Aqueduct

OBJECTIVES: We aimed to identify the causative mutation for siblings in a Korean family with nonsyndromic hearing loss (HL) and enlarged vestibular aqueduct (EVA). The siblings were a 19-year-old female with bilateral profound HL and an 11-year-old male with bilateral moderately severe HL. METHODS: We extracted genomic DNA from blood samples of the siblings with HL, their parents, and 100 controls. We performed mutation analysis for SLC26A4 using direct sequencing. RESULTS: The two siblings were compound heterozygotes with the novel mutation p.I713LfsX8 and the previously described mutation p.H723R. Their parents had heterozygous mono-allelic mutations. Father had p.I713LfsX8 mutation as heterozygous, and mother had p.H723R mutation as heterozygous. However, novel mutation p.I713LfsX8 was not detected in 100 unrelated controls. CONCLUSION: Both mutations identified in this study were located in the sulfate transporter and anti-sigma factor antagonist domain, the core region for membrane targeting of SulP/SLC26 anion transporters, which strongly suggests that failure in membrane trafficking by SLC26A4 is a direct cause of HL in this family. Our study could therefore provide a foundation for further investigations elucidating the SLC26A4-related mechanisms of HL.

The Relationship between Single Nucleotide Polymorphisms of the Carbonic Anhydrase 6 Gene andPhenylthiocarbamide Taste Sensitivity, Taste Disorder / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) taste sensitivity varies among individuals. Recently, it is reported that PROP taste responsiveness is associated with carbonic anhydrase 6 (CA6) gene polymorphism. The CA6 gene, a zinc metalloprotein in human saliva, is affected in taste function and might be correlated with gustatory diversity. The aim of this study was to examine whether PTC taste sensitivity and taste disorder is associated with the CA6 gene polymorphism rs2274327 (C/T), rs2274328 (A/C), and rs2274333 (A/G). SUBJECTS AND METHOD: A total of 217 healthy normal subjects were recruited as controls, and 50 taste disorder patients were recruited as experimental group. The polymorphisms of CA6 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. All statistical analyses were calculated using the statistical package for the social science software. Haplotypes were estimated by Haploveiw and the PHASE programs. RESULTS: The CA6 gene polymorphisms showed association with taste disorder but not with PTC sensitivity (taster/nontaster). The number of control subjects carrying AA genotype of single nucleotide polymorphism rs2274328 (A/C) in the CA6 gene was higher than the number of the subjects with taste disorder (p=0.048). However, there was no association between controls and taste disorder subjects in the haplotype analysis. CONCLUSION: These data suggest that the CA6 gene polymorphism rs2274328 could affect taste function impairment in patients with taste disorder. This observation requires a further functional study of gustin protein to clarify the association of the CA6 gene polymorphisms with the taste disorder and sensitivity.

A Family of H723R Mutation for SLC26A4 Associated with Enlarged Vestibular Aqueduct Syndrome

Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural deafness with goiter (Pendred syndrome, OMIM 274600) or NSRD with goiter (at the DFNB4 locus, OMIM 600791). H723R (2168A>G) is the most commonly reported SLC26A4 mutations in Korean and Japanese and known as founder mutation. We recently experienced one patient with enlarged vestibular aqueduct syndrome. The genetic study showed H723R homozygous in the proband and H723R heterozygous mutation in his family members. The identification of a disease-causing mutation can be used to establish a genotypic diagnosis and provide important information to both families and their physicians.

Construction of a DNA Chip for Screening of Genetic Hearing Loss

OBJECTIVES: Hearing loss is the most common sensory disorder in humans and genetic causes are estimated to cause more than 50% of all incidents of congenital hearing loss. To develop an efficient method for a genetic diagnosis of hearing loss, we have developed and validated a genetic hearing loss DNA chip that allows the simultaneous analysis of 7 different mutations in the GJB2, SLC26A4, and the mtDNA 12S rRNA genes in Koreans. METHODS: A genotyping microarray, based on the allele-specific primer extension (ASPE) method, was used and preliminary validation was examined from the five patients and five controls that were already known their genotypes by DNA sequencing analysis. RESULTS: The cutoff Genotyping index (GI) of genotyping for each mutation was set up and validated to discriminate among the genotypes. The result of the DNA chip assay was identical to those of previous results. CONCLUSION: We successfully designed the genetic hearing loss DNA chip for the first time in Korea and it would be useful for a clinical genetic diagnosis of hearing loss. Further consideration will be needed in order to examine the accuracy of this DNA chip with much larger patient sample numbers.

Angiotensinogen and Angiotensin II Type 1 Receptor Gene Polymorphism in Patients with Autosomal Dominant Polycystic Kidney Disease: Effect on Hypertension and ESRD

Autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease, is characterized by the development of hypertension and end stage renal disease. An increase in the activity of the renin-angiotensin system, due to a renal ischemia caused by cyst expansion, contributes to the development of hypertension and renal failure in ADPKD. Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease. We hypothesized that the AGT M235T and ATR A1166C polymorphisms could account for some of the variability in the progression of ADPKD. Genotyping was performed in 108 adult patients with ADPKD, and 105 normotensive healthy controls, using PCR and restriction digestion. We analyzed the effects of the AGT M235T and ATR A1166C polymorphisms on hypertension and age at the end stage renal disease (ESRD). Of the 108 patients with ADPKD, 64 (59%) had hypertension and 24 (22%) reached the ESRD. The prevalence of hypertension were; [MM+MT], [TT] genotypes, 60%, 59% (p=1.00) ; [AA], [AC+CC] genotypes, 60%, 50% respectively (p=0.54). The ages at the onset of ESRD were; [MM+MT], [TT] genotypes, 50 +/- 9 years, 56 +/- 8 years (p=0.07) ; [AA], [AC+CC] genotypes, 54 +/- 8 years, 52 +/- 14 years, respectively (p=0.07). There were no differences in the prevalence of hypertension and the ages at the ESRD in relation to the AGT M235T and ATR A1166C polymorphisms. We suggest that the AGT and ATR gene polymorphisms would not have an effect on hypertension or the ESRD in ADPKD.

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+ACU-), ID (51+ACU-) and II (34+ACU-) genotypes were similar to those of the general population. Of the 108 patients, 64 (59+ACU-) developed hypertension and 24 (22+ACU-) 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, 5510 yr in ID genotype and 529 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.

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+ACU-), ID (51+ACU-) and II (34+ACU-) genotypes were similar to those of the general population. Of the 108 patients, 64 (59+ACU-) developed hypertension and 24 (22+ACU-) 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, 5510 yr in ID genotype and 529 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.