Potential genetic modifiers of the cystic fibrosis intestinal inflammatory phenotype on mouse chromosomes 1, 9, and 10

Norkina, Oxana; Lisle, Robert C. De

doi:10.1186/1471-2156-6-29

Cited by 16 publications

(5 citation statements)

References 57 publications

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“…In the case of intestinal obstructions, it has been observed that the recurrence of meconium ileus is higher in affected siblings compared to that in unrelated patients, suggesting that genetic factors influence the manifestation of intestinal disturbances in CF. Studies designed to understand the genetic basis of the occurrence of meconium ileus have identified several genomic regions and single genes as putative modifiers in human CF patients 11 , 15 , 48 – 53 and also in CF mouse models affected by intestinal obstruction 21 , 50 , 54 , 55 .…”

Section: Discussionmentioning

confidence: 99%

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse

Philp

Riquelme

Millar-Büchner

et al. 2018

Sci Rep

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Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4, the gene encoding the calcium-activated potassium channel KCa3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells (C-kitW-sh/W-sh) and Stat6−/− to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse

Philp

Riquelme

Millar-Büchner

et al. 2018

Sci Rep

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“…We found a 36.4% of concordance for MI in sib-pairs, i.e., 4 pairs were concordant for MI and 7 pairs were discordant suggesting that in addition to the CFTR genotype other non-genetic and genetic factors contribute to the development of MI. Among the genetic ones, in CFTR-deficient mice, that is an excellent model for human MI, three potential modifier loci for MI were found on chromosomes 1, 9 and 10, respectively [47]. Subsequent studies in humans identified at least 2 modifier loci for MI [15] and thus, the SLC4A4 gene was candidate as modifier genes for MI in patients with CF [48].…”

Section: Resultsmentioning

confidence: 99%

Clinical expression of cystic fibrosis in a large cohort of Italian siblings

Terlizzi

Lucarelli

Salvatore³

et al. 2018

BMC Pulm Med

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BackgroundA clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF.MethodsWe investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis.ResultsSevere lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the “whole” CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency.ConclusionsPhysicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.Electronic supplementary materialThe online version of this article (10.1186/s12890-018-0766-6) contains supplementary material, which is available to authorized users.

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“…One of the most obvious effects of CF is poor body weight gain in early life. Although CF mice are pancreatic sufficient, in contrast to most CF patients, CF mice are about 70% the mass of WT mice from before weaning into early adulthood [ 27 ]. Lubiprostone was administered for 2 weeks and body weight gain was measured in WT and CF mice.…”

Section: Resultsmentioning

confidence: 99%

Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype

2010

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BackgroundCystic fibrosis (CF) is caused by mutations in the CFTR gene that impair the function of CFTR, a cAMP-regulated anion channel. In the small intestine loss of CFTR function creates a dehydrated, acidic luminal environment which is believed to cause an accumulation of mucus, a phenotype characteristic of CF. CF mice have small intestinal bacterial overgrowth, an altered innate immune response, and impaired intestinal transit. We investigated whether lubiprostone, which can activate the CLC2 Cl- channel, would improve the intestinal phenotype in CF mice.MethodsCftrtm1UNC (CF) and wildtype (WT) littermate mice on the C57BL/6J background were used. Lubiprostone (10 μg/kg-day) was administered by gavage for two weeks. Mucus accumulation was estimated from crypt lumen widths in periodic acid-Schiff base, Alcian blue stained sections. Luminal bacterial load was measured by qPCR for the bacterial 16S gene. Gastric emptying and small intestinal transit in fasted mice were assessed using gavaged rhodamine dextran. Gene expression was evaluated by Affymetrix Mouse430 2.0 microarray and qRT-PCR.ResultsCrypt width in control CF mice was 700% that of WT mice (P < 0.001). Lubiprostone did not affect WT crypt width but, unexpectedly, increased CF crypt width 22% (P = 0.001). Lubiprostone increased bacterial load in WT mice to 490% of WT control levels (P = 0.008). Conversely, lubiprostone decreased bacterial overgrowth in CF mice by 60% (P = 0.005). Lubiprostone increased gastric emptying at 20 min postgavage in both WT (P < 0.001) and CF mice (P < 0.001). Lubiprostone enhanced small intestinal transit in WT mice (P = 0.024) but not in CF mice (P = 0.377). Among other innate immune markers, expression of mast cell genes was elevated 4-to 40-fold in the CF intestine as compared to WT, and lubiprostone treatment of CF mice decreased expression to WT control levels.ConclusionsThese results indicate that lubiprostone has some benefits for the CF intestinal phenotype, especially on bacterial overgrowth and the innate immune response. The unexpected observation of increased mucus accumulation in the crypts of lubiprostone-treated CF mice suggests the possibility that lubiprostone increases mucus secretion.

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Potential genetic modifiers of the cystic fibrosis intestinal inflammatory phenotype on mouse chromosomes 1, 9, and 10

Cited by 16 publications

References 57 publications

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse

Clinical expression of cystic fibrosis in a large cohort of Italian siblings

Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype

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