The hepcidin gene promoter nc.-1010C > T; −582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE gene

Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 μg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group. Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance.     

Detection of the gubernacular canal and its attachment to the dental follicle may indicate an abnormal eruption status

Objectives:To evaluate and compare the detection of gubernacular canals (GC) and their characteristics in normal and abnormal tooth eruption.Materials and Methods:Patients with unerupted teeth were classified according to sex and age. Each tooth was classified according to dental group, eruption status, formation status, angulation, and GC detection. The opening of the GC in the alveolar crest and the attachment sites in relation to the dental follicle were assessed. Data were analyzed by the chi-square and Kruskal-Wallis tests, with a significance level of 5%.Results:Cone-beam computed tomography scans of 159 patients were evaluated. The final sample (N = 598) consisted of 423 teeth with normal eruption, 140 impacted teeth, and 35 teeth with delayed eruption. The overall detection rate of GC was 90.6%. These rates were 94.1%, 87.1%, and 62.9% for normal eruption, impacted teeth, and delayed eruption, respectively. GC detection rates were higher in the early stages of tooth formation in normal tooth eruption and in impacted teeth. The rate of GC detection was even lower in delayed teeth when they were angulated. Unusual attachment sites of the GC to the dental follicle were associated with abnormal eruption status.Conclusions:The results of the present study suggest that GC characteristics may indicate an abnormal eruption status.     

Chloride Conductance,Nasal Potential Difference and Cystic Fibrosis Pathophysiology

Purpose

Cystic fibrosis (CF) is a multisystem genetic disease caused by dysfunction of the epithelial anionic channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Decreased mucociliary clearance because of thickened mucus is part of the pulmonary disease pathophysiology. It is controversial if the thickened airway surface liquid (ASL) is caused by the deficient chloride secretion and excessive sodium (through ENaC) and water hyperabsorption from the periciliar fluid or by the lack of bicarbonate secretion with relative acidification of the ASL. Correlations between the magnitude of in vivo chloride conductance with phenotypic characteristics and CF genotype can help to elucidate these mechanisms and direct to new treatments.

Methods

Nasal potential difference was measured in 28 CF patients (age from 0.3 to 28 year) and correlated with pulmonary function, pancreatic phenotype, pulmonary colonization and genotype severity.

Results

The CFTR-chloride conductance was better in older patients (r = 0.40; P = 0.03), in patients with better pulmonary function (r = 0.48; P = 0.01), and was associated with genotype severity. Higher chloride diffusion in the presence of a favorable chemical gradient was associated with Pseudomonas aeruginosa negativity (P < 0.05). More negative NPDmax was associated with pancreatic insufficiency (P < 0.01) as well with genotype severity, but not with the pulmonary function.

Conclusions

The anion permeability through CFTR, mainly chloride, but bicarbonate as well, is the most critical factor in CF airway pathophysiology. Treatments primarily directed to correct CFTR function and/or airway acidity are clearly a priority.