6-n-propylthiouracil taste disruption and TAS2R38 nontasting form in Parkinson's disease.

BACKGROUND: The few studies that evaluated taste function in Parkinson's disease (PD) showed inconsistent results. The inherited ability to taste the bitter compound of 6-n-propylthiouracil has been considered to be a paradigm of general taste perception. 6-n-propylthiouracil taste perception is mediated by the TAS2R38 receptor, and reduced 6-n-propylthiouracil sensitivity has been associated with several diseases not typically related to taste function. OBJECTIVES: We evaluated the 6-n-propylthiouracil taste perception and the TAS2R38 gene as genetic risk factors for the development of idiopathic PD in PD patients and healthy controls (HC). METHODS: The 6-n-propylthiouracil taste perception was assessed by testing the responsiveness, and the ability to recognize, 6-n-propylthiouracil and sodium chloride. The participants were classified for 6-n-propylthiouracil taster status and genotyped for the TAS2R38 gene. RESULTS: A significant increase in the frequency of participants classified as 6-n-propylthiouracil nontasters and a reduced ability to recognize bitter taste quality of 6-n-propylthiouracil were found in PD patients when compared with healthy controls. The results also showed that only 5% of PD patients had the homozygous genotype for the dominant tasting variant of TAS2R38, whereas most of them carried the recessive nontaster form and a high number had a rare variant. CONCLUSIONS: Our results show that 6-n-propylthiouracil taster status and TAS2R38 locus are associated with PD. The 6-n-propylthiouracil test may therefore represent a novel, simple way to identify increased vulnerability to PD. Moreover, the presence of the nontasting form of TAS2R38 in PD may further substantiate that disease-associated taste disruption may represent a risk factor associated with the disease. © 2018 International Parkinson and Movement Disorder Society.

Chk2 deficiency alleviates irradiation-induced taste dysfunction by inhibiting p53-dependent apoptosis.

OBJECTIVE: Taste dysfunction is one of the most common complications following radiotherapy, which leads to decreased appetite and life quality of patients suffering from head and neck cancer. The aim of this study was to investigate the role of checkpoint kinase 2 (Chk2) deficiency in irradiation-induced taste dysfunction. MATERIALS AND METHODS: Alterations in oxidative stress, DNA damage, and potential signaling pathway were compared between Chk2-deficient (Chk2-/- ) mice and their wild-type (WT) littermates pre-irradiation and 7 and 30 days postirradiation by biochemistry and immunohistochemistry. RESULTS: Chk2-/- mice showed less loss of type II and type III taste cells, lower expression of p53, caspase-3, and cleaved caspase-3, and lower apoptosis levels. However, no significant differences in H2 O2 and MDA concentrations, T-SOD and GSH-Px activities, and expression of SOD1, SOD2, and 8-OHdG were detected in the taste buds of Chk2-/- mice as compared to those of WT mice. CONCLUSION: Chk2 deficiency downregulated the expression of p53 and inhibited cellular apoptosis, partly contributing to the radioprotective effect on taste cells, but did not alter oxidative stress levels, antioxidant ability, and oxidative DNA damage in taste buds.

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia.

PURPOSE: Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS: Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS: Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS: Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls.

Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands.

Drug-induced taste disturbance is a common adverse drug reaction often triggered by drug secretion into saliva. Very little is known regarding the molecular mechanisms underlying salivary gland transport of xenobiotics, and most drugs are assumed to enter saliva by passive diffusion. In this study, we demonstrate that salivary glands selectively and highly express OCT3 (organic cation transporter-3), a polyspecific drug transporter in the solute carrier 22 family. OCT3 protein is localized at both basolateral (blood-facing) and apical (saliva-facing) membranes of salivary gland acinar cells, suggesting a dual role of this transporter in mediating both epithelial uptake and efflux of organic cations in the secretory cells of salivary glands. Metformin, a widely used anti-diabetic drug known to induce taste disturbance, is transported by OCT3/Oct3 in vitro. In vivo, metformin was actively transported with a high level of accumulation in the salivary glands of wild-type mice. In contrast, active uptake and accumulation of metformin in salivary glands were abolished in Oct3(-/-) mice. Oct3(-/-) mice also showed altered metformin pharmacokinetics and reduced drug exposure in the heart. These results demonstrate that OCT3 is responsible for metformin accumulation and secretion in salivary glands. Our study uncovered a novel carrier-mediated pathway for drug entry into saliva and sheds new light on the molecular mechanisms underlying drug-induced taste disorders.

Patients with phantogeusia show increased expression of T2R taste receptor genes in their tongues.

OBJECTIVES: The taste receptor gene family T2R has been implicated in the sensation of bitter taste. Phantogeusia is a spontaneous abnormal taste with no external stimulus. We analyzed the expression of T2R taste receptor genes in the tongues of patients with phantogeusia to assess their role in the pathogenesis of phantogeusia. METHODS: We obtained specimens from 43 patients with phantogeusia and 24 normal volunteers by scraping the foliate papillae and examined these specimens for the expression of 10 T2R taste receptor genes using reverse transcription-polymerase chain reaction and electrophoresis. RESULTS: The expression rate (subjects with detectable expression) of the 10 taste receptor genes in the healthy subjects ranged from 16.7% to 100%; 3 receptor genes were found in 50% or fewer of these subjects. In the patients with phantogeusia, the expression rate was increased significantly compared to that in the healthy control subjects for 3 of the 10 receptor genes examined. CONCLUSIONS: Our results show that the expression rate of some of the T2R taste receptor genes was increased significantly in patients with phantogeusia. These results suggest that increased expression of taste receptor genes is involved in the pathogenesis of phantogeusia; this finding may contribute to elucidation of the mechanism of this disorder.

Bitter Taste Receptors and Chronic Otitis Media.

OBJECTIVE: To evaluate the presence of bitter taste receptors (T2Rs) in the middle ear and to examine their relationship with chronic ear infections. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care hospital. METHODS: This study enrolled 84 patients being evaluated for otologic surgery: 40 for chronic otitis media (COM) and 44 for other surgical procedures (controls). We collected a small piece of mucosa from 14 patients for mRNA analysis and from 23 patients for immunohistochemistry. A total of 55 patients underwent a double-blind taste test to gauge sensitivity to phenylthiocarbamide, denatonium, quinine, sucrose, and sodium chloride; 47 patients gave a salivary sample for single-nucleotide polymorphism analysis of rs1376251 (TAS2R50) and rs1726866 (TAS2R38). RESULTS: Bitter taste receptors were found in all samples, but the repertoire varied among patients. T2R50 was the most consistently identified receptor by mRNA analysis. Its rs1376251 allele was related to susceptibility to COM but not the expression pattern of T2R50. Ratings of bitterness intensity of phenylthiocarbamide, a ligand for T2R38, differed significantly between the COM and control groups. CONCLUSION: T2Rs were found within the middle ear of every patient sampled; the rs1376251 allele of TAS2R50 appears to be related to chronic ear infections. These receptors are an intriguing target for future research and possible drug targeting.

Taste Changes in Patients with Inflammatory Bowel Disease: Associations with PROP Phenotypes and polymorphisms in the salivary protein, Gustin and CD36 Receptor Genes.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract resulting from interactions among various factors with diet being one of the most significant. IBD-related dietary behaviors are not clearly related to taste dysfunctions. We analyzed body mass index (BMI) and perception of six taste qualities and assessed effects of specific taste genes in IBD patients and healthy subjects (HC). BMI in IBD patients was higher than in HC subjects. Taste sensitivity to taste qualities was reduced in IBD patients, except for sour taste, which was higher than in HC subjects. Genetic variations were related to some taste responses in HC subjects, but not in IBD patients. Frequencies of genotype AA and allele A in CD36 polymorphism (rs1761667) were significantly higher in IBD patients than in HC subjects. The taste changes observed could be explained by the oral pathologies and microbiome variations known for IBD patients and can justify their typical dietary behaviors. The lack of genetic effects on taste in IBD patients indicates that IBD might compromise taste so severely that gene effects cannot be observed. However, the high frequency of the non-tasting form of CD36 substantiates the fact that IBD-associated fat taste impairment may represent a risk factor for IBD.

Selective Peripheral Taste Dysfunction in APP/PS1 Mutant Transgenic Mice.

BACKGROUND: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer's disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two. OBJECTIVE: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information. METHODS: The APP/PS1 transgenic mutant mice were used as a model of Alzheimer's disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits. RESULTS: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons' peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells. CONCLUSION: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD.

Chemosensory Dysfunction in COVID-19: Integration of Genetic and Epidemiological Data Points to D614G Spike Protein Variant as a Contributing Factor.

After several months of rapid pandemic expansion, it is now apparent that the SARS-CoV-2 coronavirus interferes with smell and taste sensation in a substantial proportion of COVID-19 patients. Recent epidemiological data documented intriguing differences in prevalence of chemosensory dysfunctions between different world regions. Viral genetic factors as well as host genetic factors appear to be relevant; however, it is not yet known which mutations or polymorphisms actually contribute to such phenotypic differences between populations. Here, we discuss recent genetic and epidemiological data on the D614G spike protein variant and assess whether current evidence is consistent with the notion that this single nucleotide polymorphism augments chemosensory impairments in COVID-19 patients. We hypothesize that this spike variant is an important viral genetic factor that facilitates infection of chemosensory epithelia, possibly acting together with yet to be identified host factors, and thereby increases smell and taste impairment. We suggest that the prevalence of chemosensory deficits may reflect the pandemic potential for transmissibility and spread which differs between populations.

Taste disorders are partly genetically determined: Role of the TAS2R38 gene, a pilot study.

OBJECTIVES/HYPOTHESIS: Taste sensitivity varies greatly among individuals influencing eating behavior and health, consequently the disorders of this sense can affect the quality of life. The ability to perceive the bitter of thiourea compounds, such as phenylthiocarbamide (PTC), has been largely reported as a marker of the general taste sensitivity, food preferences, and health. PTC sensitivity is mediated by the TAS2R38 receptor and its genetic common variants. We study the role of the TAS2R38 receptor in taste disorders with the aim of understanding if these can be genetically determined. STUDY DESIGN: Prospective cohort study. METHODS: Differences in the PTC responsiveness between the patients cohort and healthy controls were assessed. All subjects received standardized tests for smell and taste function and were genotyped for the TAS2R38 gene. RESULTS: PAV/PAV homozygous patients gave high PTC ratings, whereas PAV/AVI genotypes reported lower values, which are similar to those determined in AVI/AVI or rare genotypes. In addition, the patients cohort did not meet the Hardy-Weinberg equilibrium at the TAS2R38 locus, showing a very low frequency of subjects carrying the PAV/AVI diplotype. Independently, in healthy controls who were in equilibrium at the locus, PAV/PAV homozygous and heterozygous rated PTC bitterness higher compared to AVI/AVI or rare genotypes. CONCLUSIONS: Our findings, by showing that an only taster haplotype (PAV) is not sufficient to evoke high responses of TAS2R38 receptor in patients with taste disorders, suggest that the genetic constitution may represent a risk factor for the development of taste disorders. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:E307-E312, 2019.

Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease.

Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared with wild-type mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion.

Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype.

Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family ( n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations ( n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.

Dystonin deficiency reduces taste buds and fungiform papillae in the anterior part of the tongue.

The anterior part of the tongue was examined in wild type and dystonia musculorum mice to assess the effect of dystonin loss on fungiform papillae. In the mutant mouse, the density of fungiform papillae and their taste buds was severely decreased when compared to wild type littermates (papilla, 67% reduction; taste bud, 77% reduction). The mutation also reduced the size of these papillae (17% reduction) and taste buds (29% reduction). In addition, immunohistochemical analysis demonstrated that the dystonin mutation reduced the number of PGP 9.5 and calbindin D28k-containing nerve fibers in fungiform papillae. These data together suggest that dystonin is required for the innervation and development of fungiform papillae and taste buds.

Genetic variation in bitter taste receptor gene TAS2R38, PROP taster status and their association with body mass index and food preferences in Indian population.

Polymorphisms in bitter taste receptor gene TAS2R38 alter the ability to sense the intensity of bitterness of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). Genetic variation in sensitivity towards PTC and PROP may affect food preferences and susceptibility to certain diseases. This is the first study aimed at investigating frequency and distribution of TAS2R38 haplotypes in an Indian cohort. Additionally, we studied the association of TAS2R38 and PROP taster status with BMI and food preference. Three hundred and ninety three healthy adults who were 19-55years of age were selected as a convenience sample from 4 geographical regions of India. Single nucleotide polymorphisms (SNPs) of TAS2R38 (rs713598, s1726866 and rs10246939) were analyzed using polymerase chain reaction-restriction fragment length polymorphism. The prevalence of PAV/PAV diplotype was 9.9% and that of AVI/AVI diplotype was 43.76% among this Indian population. PROP status was determined on the basis of its threshold concentration of detecting bitterness, as evaluated by one-solution test. The PROP status revealed 25.95% supertasters, 32.06% medium tasters and 41.98% non-tasters (NT). BMI neither significantly (p>0.05) correlated with TAS2R38 genotypes nor with PROP taster status. Food preferences did not significantly (p>0.05) correlate with TAS2R38 diplotypes or PROP phenotypes.

Clinical Significance of Umami Taste and Umami-Related Gene Expression Analysis for the Objective Assessment of Umami Taste Loss.

Loss of umami taste sensation affects quality of life and causes weight loss and health problems, particularly in the elderly. We recently expanded the use of the filter paper disc method to include assessment of umami taste sensitivity, using monosodium glutamate as the test solution. This test showed high diagnostic performance for discriminating between normal taste function and disorders in sensation of the umami taste, according to established cut-off values. The test also revealed: (1) some elderly patients suffered from specific loss of umami taste sensation with preservation of the other four taste sensations (sweet, salty, sour, and bitter); (2) umami taste disorder caused a loss of appetite and decline in weight, resulting in poor health; (3) appetite, weight and overall health improved after appropriate treatment for umami taste disorder. Because of the subjective nature of the test, however, it may not be useful for patients who cannot express which taste sensation is induced by a tastant, such as those with dementia. Most recently, using tissue samples collected from the tongue by scraping the foliate papillae, we showed that evaluation of umami taste receptor gene expression may be clinically useful for the objective genetic diagnosis of umami taste disorders.

Phenylthiocarbamide perception in patients with schizophrenia and first-degree family members.

OBJECTIVE: The inability to taste phenylthiocarbamide (PTC) has been associated with medical and neurological illnesses not typically related to taste. The authors examined PTC sensitivity in schizophrenia patients and their non-ill relatives to determine whether this represented a vulnerability marker. METHOD: PTC sensitivity was assessed in 42 schizophrenia patients, 23 healthy comparison subjects, and 12 first-degree relatives of the patients. RESULTS: More nontasters were found among patients and family members than healthy comparison subjects. Among patients, nontasters had more positive symptoms. Differences were not explained by sex, age, medication, smoking, or cognitive impairment. CONCLUSIONS: The prevalence of PTC nontasters was greater among schizophrenia patients and non-ill first-degree family members. Phenotypic variation in PTC sensitivity is genetic in origin. This suggests a higher risk for illness among subjects with recessive alleles.

PROP (6-n-propylthiouracil) supertasters and the saltiness of NaCl.

Taste blindness to phenylthiocarbamide (PTC) and its chemical relative 6-n-propylthiouracil (PROP) was discovered in the 1930s. Family studies showed that those who could not taste PTC/PROP (nontasters) carried two recessive alleles. In recent years, we have classified tasters into two groups: medium (PROP is moderately bitter) and supertasters (PROP is intensely bitter). With our classification, approximately 25% of Americans are nontasters, 50%, medium tasters, and 25%, supertasters. Studies showed that supertasters form a cohesive group. Anatomical studies showed that supertasters have the most fungiform papillae. Psychophysical studies showed that supertasters perceive the most intense bitterness and sweetness from a variety of compounds, the most intense burn from oral irritants, and the most intense tactile sensations from viscous solutions. Oral burn and touch are presumably perceived to be the most intense to supertasters because taste buds in fungiform papillae are innervated by the trigeminal nerve (pain, touch) as well as the chorda tympani nerve (taste). The psychophysical scaling method used was magnitude matching with NaCl as the control modality. With this method, subjects rated the intensities of a series of NaCl and PROP solutions. The assumption that the taste of NaCl did not vary with PROP status allowed comparisons of the bitterness of PROP across subjects. Early magnitude matching studies, using sound as the control, had suggested that this assumption was reasonable. However, recent studies challenged that conclusion. Larger samples with more diverse populations, using sound as the control, showed that the taste of NaCl varied with PROP bitterness; supertasters perceived the strongest taste and nontasters, the weakest. Thus our earlier conclusions were conservative because differences between nontasters, medium tasters, and supertasters were concealed by using NaCl as a standard. Using magnitude matching with sound as the standard, or using the Green scale, which employs intensity labels, we found that the differences between PROP groups are larger. Note that the association between PROP status and salt taste is interesting in itself, since variability in salt taste may have important nutritional consequences.

Genetics of human taste perception.

Genetic approaches are rapidly yielding new information about our sense of taste. This information comes from both molecular studies of genes encoding taste receptors and other taste-signaling components, and from studies of inherited variation in taste abilities. Our understanding of bitter taste has advanced by combined information from discovery and study of the TAS2R family of taste receptor genes, hand in hand with genetic linkage and positional cloning studies, notably on the ability to taste phenylthiocarbamide (PTC). Sweet and umami tastes, mediated by TAS1R receptors, are becoming well-characterized at the molecular genetic level, and these taste classes are now targets for linkage, positional cloning, and genetic association strategies. Salty and sour tastes are still poorly characterized in genetic terms, and represent opportunities for the future.

Young women's food preferences and taste responsiveness to 6-n-propylthiouracil (PROP).

This study examined links between taste responsiveness to 6-n-propylthiouracil (PROP), a heritable trait, and sensory responses to six common foods. Sixty-three young women subjects were divided into PROP tasters (n = 25) and nontasters (n = 25), based on their responses to PROP-impregnated filter paper and mean bitterness intensity ratings for seven PROP solutions. Thirteen subjects were excluded as unclassifiable. The 50 subjects sampled Brussels sprouts, broccoli, spinach, black coffee, soy milk, and soybean tofu. Sensory ratings for bitter intensity; pleasantness of taste, odor, and texture, and overall food acceptability scores were obtained using nine-point category scales. All subjects completed a food-preference checklist and a modified food-frequency questionnaire. PROP tasters rated Brussels sprouts as more bitter than did nontasters (p<0.05). Subjects who perceived the foods as more bitter also rated them as less pleasant and less acceptable. Taste preferences and food preferences were linked. Self-reported food preferences and self-reported frequencies of consumption for the same foods were also linked. Taste factors and food preferences may impact dietary choices and the frequency of food consumption.