Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis

Lam, Anh Thu N.; Aksit, Melis A.; Vecchio-Pagán, Briana; Shelton, Celeste; Osorio, Derek L.; Anzmann, Arianna F.; Goff, Loyal A.; Whitcomb, David C.; Blackman, Scott M.; Cutting, Garry R.

doi:10.1172/jci129833

Cited by 39 publications

(35 citation statements)

References 94 publications

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“…Interestingly, as the SLC26A9 gene is also associated with the risk of onset of MI at birth (see above) this suggests a pleiotropic action of this gene [41] . Finally, a recent study provides new data suggestive of an impact of SLC26A9 promoter variants on its expression [46] .…”

Section: Modifiers Of Cystic Fibrosis Related Diabetes (Cfrd)mentioning

confidence: 87%

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

Paranjapye

Ruffin

Harris

et al. 2020

Journal of Cystic Fibrosis

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In patients with cystic fibrosis (CF), genetic variants within and outside the CFTR locus contribute to the variability of the disease severity. CFTR transcription is tightly regulated by cis-regulatory elements (CREs) that control the three-dimensional structure of the locus, chromatin accessibility and transcription factor recruitment. Variants within these CREs may contribute to the pathophysiology and to the phenotypic heterogeneity by altering CFTR transcript abundance. In addition to the CREs, variants outside the CFTR locus, namely "modifiers genes", may also be associated with the clinical variability. This review addresses variants at the CFTR locus itself and CFTR CREs, together with the outcomes of the latest modifier gene studies with respect to the different CF phenotypes.

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Section: Modifiers Of Cystic Fibrosis Related Diabetes (Cfrd)mentioning

confidence: 87%

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

Paranjapye

Ruffin

Harris

et al. 2020

Journal of Cystic Fibrosis

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“…Furthermore, a recent study demonstrated that increased SLC26A9 expression in pancreatic ductal cells delays the age of onset of CF-related diabetes. 242 …”

Section: Modulation Of Alternative (Non-cftr) Channels/transportersmentioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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“…This variant was described in association with pancreatic insufficiency and early exocrine pancreatic disease in CF patients [ 118 ]. Expression studies showed that SLC26A9 and CFTR interact reciprocally under both physiological and pathophysiological conditions [ 117 , 119 ]. Other studies suggested that SLC26A9 may be able to compensate for the CFTR dysfunction in CF patients [ 117 ].…”

Section: Genetic Factorsmentioning

confidence: 99%

Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors

et al. 2021

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Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride/bicarbonate channel expressed on the membrane of epithelial cells of the airways and of the intestine, as well as in cells with exocrine and endocrine functions. A common nonpulmonary complication of CF is cystic fibrosis-related diabetes (CFRD), a distinct form of diabetes due to insulin insufficiency or malfunction secondary to destruction/derangement of pancreatic betacells, as well as to other factors that affect their function. The prevalence of CFRD increases with age, and 40–50% of CF adults develop the disease. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas, as well as contrasting theories on the direct or indirect impact of CFTR mutation on islet function. Among contributors to the development of CFRD, in addition to CFTR genotype, there are other genetic factors related and not related to type 2 diabetes. This review presents an overview of the current understanding on genetic factors associated with glucose metabolism abnormalities in CF.

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Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis

Cited by 39 publications

References 94 publications

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors

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