Mucins are excellent candidates for contributing to the presence of meconium ileus (MI) in cystic fibrosis (CF) due to their extensive genetic variation and known function in intestinal physiology. The length of variants in mucin central repetitive regions has not been explored as "risk" factors for MI in CF.
We investigated the length polymorphisms in the central repetitive regions of MUC1, MUC2, and MUC5AC by Southern blot and tested for association with MI in CF subjects.
No significant associations were found for the allele sizes of any of the genes with respect to the prevalence of MI (p values=0.33, 0.16, and 0.71 for MUC1, MUC2, and MUC5AC, respectively).
The genetic length variants in the central repetitive region of three MUC genes studied are not associated with MI in subjects with CF.
[Show abstract][Hide abstract] ABSTRACT: Background. Tacrolimus (FK506) is effective for patients with ulcerative colitis (UC). However, there are few reports on tacrolimus therapy (TT) with respect to the relationship with endoscopic and clinicopathologic findings. Methods. Thirty patients with moderate/severe active UC refractory to or dependent on corticosteroid were treated with oral tacrolimus. The expression of ectopic MUC5AC in the colon was pathologically analyzed before and at 12 weeks after TT, evaluating the Mayo score and steroid-sparing effects. Results. Both mean disease and endoscopic activity index scores were reduced at levels of statistical significance in 26 UC patients receiving more than one month of TT (P < 0.0001). The dose of prednisolone was reduced by a statistically significant amount (P = 0.00022), and 14 of the 26 patients (53.8%) had steroid-free status 12 weeks after TT. The decrease in ectopic MUC5AC expression in the mucous cells of the colon was significantly associated with endoscopic improvement of inflammation in the UC patients with TT (P = 0.043). Loss of ectopic MUC5AC expression was detected in all patients who had complete response. Conclusions. Tacrolimus appears to be effective for the treatment of moderate/severe UC patients. Loss of ectopic MUC5AC expression may be important for pathologic remission in the colon of UC patients.
[Show abstract][Hide abstract] ABSTRACT: Salmonella enterica serovar Typhimurium is a model organism used to explore the virulence strategies underlying Salmonella pathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection against Salmonella is still unclear. The intestinal mucus layer is primarily composed of the Muc2 mucin, a heavily O-glycosylated glycoprotein. Muc2's core 3- O derived glycans are synthesized by Core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2, but display a thinner intestinal mucus barrier. We began our investigations by comparing Salmonella induced colitis and mucus dynamics in Muc2 deficient (-/-) mice, C3GnT -/- mice and wildtype C57BL/6 (WT) mice. Salmonella infection led to an increase in luminal Muc2 secretion in WT and C3GnT-/- mice. When Muc2 -/- mice were infected with Salmonella, they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and developing significantly increased barrier disruption and high mortality rates compared with WT mice. We found the exaggerated barrier disruption in infected Muc2-/- mice was invA dependent. We also tested the susceptibility of C3GnT -/- mice, finding they carried similar pathogen burdens to WT mice but developed exaggerated barrier disruption. Moreover, we found that Muc2 -/- mice were impaired in intestinal alkaline phosphatase (IAP) expression and LPS detoxification activity in their ceca, potentially explaining their high mortality rates during infection. Our data suggests that the intestinal mucus layer (Muc2) and core 3-O glycosylation play a critical role in controlling Salmonella intestinal burdens and intestinal epithelial barrier function respectively.
Infection and immunity 07/2013; 81(10). DOI:10.1128/IAI.00854-13 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Technological advances in genetics have made feasible and affordable large studies to identify genetic variants that cause or modify a trait. Genetic studies have been carried out to assess variants in candidate genes, as well as polymorphisms throughout the genome, for their associations with heritable clinical outcomes of cystic fibrosis (CF), such as lung disease, meconium ileus, and CF-related diabetes. The candidate gene approach has identified some predicted relationships, while genome-wide surveys have identified several genes that would not have been obvious disease-modifying candidates, such as a methionine sulfoxide transferase gene that influences intestinal obstruction, or a region on chromosome 11 proximate to genes encoding a transcription factor and an apoptosis controller that associates with lung function. These unforeseen associations thus provide novel insight into disease pathophysiology, as well as suggesting new therapeutic strategies for CF.
Cold Spring Harbor Perspectives in Medicine 12/2012; 2(12). DOI:10.1101/cshperspect.a009548 · 9.47 Impact Factor
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