WNT10A variants: following the pattern of inheritance in tooth agenesis and self-reported family history of cancer.

OBJECTIVES: The aim of this study was the analysis of WNT10A variants in seven families of probands with various forms of tooth agenesis and self-reported family history of cancer. MATERIALS AND METHODS: We enrolled 60 young subjects (aged 13 to 17) from the Czech Republic with various forms of tooth agenesis. Dental phenotypes were assessed using Planmeca ProMax 3D (Planmeca Oy, Finland) with Planmeca Romexis software (version 2.9.2) together with oral examinations. After screening PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes on the Illumina MiSeq platform (Illumina, USA), we further analyzed the evolutionarily highly conserved WNT10A gene by capillary sequencing in the seven families. RESULTS: All the detected variants were heterozygous or compound heterozygous with various levels of phenotypic expression. The most severe phenotype (oligodontia) was found in a proband who was compound heterozygous for the previously identified WNT10A variant p.Phe228Ile and a newly discovered c.748G > A variant (p.Gly250Arg) of WNT10A. The newly identified variant causes substitution of hydrophobic glycine for hydrophilic arginine. CONCLUSIONS: We suggest that the amino acid changes in otherwise highly conserved sequences significantly affect the dental phenotype. No relationship between the presence of WNT10A variants and a risk of cancer has been found. CLINICAL RELEVANCE: Screening of PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes in hope to elucidate the pattern of inheritance in families.

An association of neovascular age-related macular degeneration with polymorphisms of CFH, ARMS2, HTRA1 and C3 genes in Czech population.

PURPOSE: We investigated associations between neovascular age-related macular degeneration (AMD) and rs10490924 polymorphism of ARMS2 gene (age-related maculopathy susceptibility 2), rs1061170 polymorphism of gene for complement factor H (CFH), rs2230199 polymorphism of gene for complement component C3 and rs11200638 polymorphism of gene for serine protease high-temperature requirement A1 (HTRA1) in the Czech population. METHODS: We analysed samples of DNA from 307 patients diagnosed with neovascular form of late AMD (average age: 73.7 ± 7.7 years) and 191 control subjects, recruited from patients awaiting cataract surgery (average age, 73.6 ± 8.7 years). RESULTS: HTRA1, CFH and ARMS2 genes polymorphisms were found to be related to neovascular AMD in the Czech population. All analysed polymorphisms were statistically significantly associated with neovascular AMD, with stronger associations in females than in males. In whole group, CC genotype of CFH gene polymorphism, TT genotype of ARMS2 gene polymorphism and AA genotype of HTRA1 gene polymorphism showed the greatest risk for neovascular AMD with odds ratios equal to 8.43, 10.07, 9.83, respectively (p < 0.0001). Only CG polymorphism of C3 gene showed statistically significant risk for neovascular AMD. In addition, we observed an association between waist circumference and neovascular AMD in both sexes, which further suggests the significance of excessive abdominal fat as a risk factor of AMD. We found a statistically significant association between polymorphisms in HTRA1, CFH and ARMS2 genes and neovascular AMS in the Czech population. The association was stronger in females than in males. CONCLUSION: We demonstrated a relationship between neovascular AMD and genes for HTRA1, CFH, ARMS2 and C3 in Czech population. To our knowledge, the relationship between these polymorphisms and neovascular AMD in Czech population has never been investigated before.

CD36 gene is associated with intraocular pressure elevation after intravitreal application of anti-VEGF agents in patients with age-related macular degeneration: Implications for the safety of the therapy.

BACKGROUND: The wet form of age-related macular degeneration (AMD) is characterized by pathological vascularization of the outer retinal layers. The condition responds to treatment with antibodies against vascular endothelial growth factor (VEGF), but the patients receiving such anti-VEGF therapy sometimes show undesirable acute short-term increases in the intraocular pressure (IOP). The cause of this adverse effect is unknown, and here, we are testing a hypothesis that it is related to CD36 gene polymorphisms. MATERIALS AND METHODS: A group of 134 patients with AMD were given three therapeutic doses of anti-VEGF antibody (ranibizumab) at monthly intervals. Their IOP was measured immediately before and 30 min after each injection. Patients' DNA was analyzed, and the changes in IOP were matched against seven polymorphisms of the CD36 gene. RESULTS: Three polymorphisms were found to be associated with increases in IOP: rs1049673 (p = 0.006), rs3211931 (p = 0.01), and rs1761667 (p = 0.043) at the time of the third injection only. Pronounced elevations (IOP > 25 mmHg) were associated with rs1049673 polymorphism: GC genotype (p < 0.01) and CC genotype (p < 0.05); both increasing the risk 2.6-fold, the presence of C-allele conferring a 1.5-fold greater risk and with rs3211931 polymorphism: AG genotype (p < 0.01) and GG genotype (p < 0.05); increasing the risk 2.6-fold (AG) and 2.7-fold (GG). CONCLUSIONS: CD36 receptor may be involved in mediating the effects of VEGF on IOP. The findings will help to identify the patients at risk of acutely elevated IOP following the anti-VEGF therapy.

Mutations in AXIN2 gene as a risk factor for tooth agenesis and cancer: A review.

AXIN2 gene plays a crucial role in morphogenesis of craniofacial area and is essential for tooth development. AXIN2 gene is one of the most studied genes associated with tooth agenesis, the most common defect of dentition in humans. Polymorphic variants in AXIN2 gene are discussed in relation to the occurrence of the tooth agenesis but also as an indication of the risk of cancer. Mutations in AXIN2 gene were found in patients with colorectal or hepatocellular carcinoma, prostate cancer, ovarium or lung cancer. These findings support the hypothesis that missing teeth may be a significant marker for predisposition for cancer.

The A allele of cluster of differentiation 36 (CD36) SNP 1761667 associates with decreased lipid taste perception in obese Tunisian women.

Recent studies have suggested that excessive intake of dietary fat is associated with obesity. Some obese subjects have been reported to exhibit high thresholds for the gustatory detection of lipids via lipid receptors, such as cluster of differentiation 36 (CD36). We studied lingual detection thresholds for emulsions containing oleic acid in obese Tunisian women (n 203) using a three-alternative forced choice (3-AFC) method. Genotyping of the TNF-α (rs1800629), IL-6 (rs1800795) and CD36 (rs1761667) genes was performed to associate with lipid taste perception thresholds. The CD36 genotype distribution was as follows: GG (n 42), AG (n 102) and AA (n 59). Women with the CD36 GG genotype exhibited oral detection thresholds for oleic acid that were more than three times lower than those with the CD36 AA genotype. The present study confirms a high threshold of gustatory fat detection in obese women with the CD36 AA genotype, but there is no significant association with the IL-6 and TNF-α gene polymorphisms.

A screen of a large Czech cohort of oligodontia patients implicates a novel mutation in the PAX9 gene.

Tooth agenesis is one of the most common developmental anomalies in humans. To date, many mutations involving paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) genes have been identified. The aim of the present study was to perform screening for mutations and/or polymorphisms using the capillary sequencing method in the critical regions of PAX9 and MSX1 genes in a group of 270 individuals with tooth agenesis and in 30 healthy subjects of Czech origin. This screening revealed a previously unknown heterozygous g.9527G>T mutation in the PAX9 gene in monozygotic twins with oligodontia and three additional affected family members. The same variant was not found in healthy relatives. This mutation is located in intron 2, in the region recognized as the splice site between exon 2 and intron 2. We hypothesize that the error in pre-mRNA splicing may lead to lower expression of PAX9 protein and could have contributed to the development of tooth agenesis in the affected subjects.

Corticotropin-releasing hormone receptor subtypes in the rat anterior pituitary after two types of restraint stress.

The stress response in anterior pituitary (AP) is mediated by corticotropin-releasing hormone (CRH) acting through CRH-R1 and -R2, however, the function of CRH-R2 in AP is still not fully elucidated. We used 1-h long restraint (IMO) as well as restraint combined with water immersion (IMO+C). Using real-time PCR we quantified mRNA expression of CRH-R1, CRH-R2alpha-soluble and -insoluble, and cAMP response element binding (CREB), with reference gene GAPDH. In control AP, CRH-R1 mRNA was up to 20-fold higher than levels of CRH-R2alpha-soluble or CRH-R2alpha-insoluble mRNA. IMO reduced CRH-R1 mRNA to 47% and 63% of control levels 1 and 2 h after the onset of stressor, respectively, while IMO+C did not produce significant changes. Our data demonstrated that these stressors did not change CRH-R2alpha mRNA, unlike the very significant response of CRH-R1 to IMO.