p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders?

Martinez, Brigitte; Marion, Heller; Gaitch, Natacha; Hubert, D.; Burgel, Pierre‐Régis; Lévy, Philippe; Girodon, Emmanuelle; Bienvenu, Thierry

doi:10.1038/jhg.2014.2

Cited by 10 publications

(3 citation statements)

References 22 publications

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“…We note, however, a slight over‐representation of the p.Arg75Gln (R75Q) in the subgroup of 18 pancreatitis patients, as 12 heterozygotes for this variant account for 3.3% of 368 alleles compared with other phenotypic subgroups (0.2%) and to the general population (MAF ≤ 2.4%). This observation is consistent with recent studies on patients affected with idiopathic chronic pancreatitis (Martinez et al., ; Schneider et al., ).…”

Section: Distribution Of Cftr Genotypessupporting

confidence: 93%

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

et al. 2017

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Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles.

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Section: Distribution Of Cftr Genotypessupporting

confidence: 93%

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

et al. 2017

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“…The comprehensive systematic search and selection process identified 22 case-control studies that reported on some or all of the 9 CFTR BD variants and met the inclusion criteria for quantitative synthesis (Fig 1) [9,11,12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. We noted significant geographic/ethnic differences in the distribution of the CFTR BD variants.…”

Section: Resultsmentioning

confidence: 99%

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Berke

Gede²,

Szadai³

et al. 2022

PLoS ONE

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Introduction Cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in pancreatic ductal fluid secretion by mediating Cl- and HCO3- ion transport across the apical membrane. Severe CFTR mutations that diminish chloride conductance cause cystic fibrosis (CF) if both alleles are affected, whereas heterozygous carrier status increases risk for chronic pancreatitis (CP). It has been proposed that a subset of CFTR variants characterized by a selective bicarbonate conductance defect (CFTRBD) may be associated with CP but not CF. However, a rigorous genetic analysis of the presumed association has been lacking. Aims To investigate the role of heterozygous CFTRBD variants in CP by meta-analysis of published case-control studies. Materials and methods A systematic search was conducted in the MEDLINE, Embase, Scopus, and CENTRAL databases for published studies that reported the CFTRBD variants p.R74Q, p.R75Q, p.R117H, p.R170H, p.L967S, p.L997F, p.D1152H, p.S1235R, and p.D1270N in CP patients and controls. Results Twenty-two studies were eligible for quantitative synthesis. Combined analysis of the 9 CFTRBD variants indicated enrichment in CP patients versus controls (OR = 2.31, 95% CI = 1.17–4.56). Individual analysis of CFTRBD variants revealed no association of p.R75Q with CP (OR = 1.12, 95% CI = 0.89–1.40), whereas variants p.R117H and p.L967S were significantly overrepresented in cases relative to controls (OR = 3.16, 95% CI = 1.94–5.14, and OR = 3.88, 95% CI = 1.32–11.47, respectively). The remaining 6 low-frequency variants gave inconclusive results when analyzed individually, however, their pooled analysis indicated association with CP (OR = 2.08, 95% CI = 1.38–3.13). Conclusion Heterozygous CFTRBD variants, with the exception of p.R75Q, increase CP risk about 2-4-fold.

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“…Two of these mutations, R74Q and R75Q, showed a reduced association with WNK1 [ 53 ]. However, more recent studies could not confirm that the R75Q mutation is a risk factor for CP, neither in the presence nor absence of a concurrent SPINK1 mutation [ 107 ].…”

Section: Bicarbonate Transport In Subjects With Cftr Mutationsmentioning

confidence: 99%

Bicarbonate Transport in Cystic Fibrosis and Pancreatitis

Angyal

Bijvelds

Bruno

et al. 2021

Cells

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CFTR, the cystic fibrosis (CF) gene-encoded epithelial anion channel, has a prominent role in driving chloride, bicarbonate and fluid secretion in the ductal cells of the exocrine pancreas. Whereas severe mutations in CFTR cause fibrosis of the pancreas in utero, CFTR mutants with residual function, or CFTR variants with a normal chloride but defective bicarbonate permeability (CFTRBD), are associated with an enhanced risk of pancreatitis. Recent studies indicate that CFTR function is not only compromised in genetic but also in selected patients with an acquired form of pancreatitis induced by alcohol, bile salts or smoking. In this review, we summarize recent insights into the mechanism and regulation of CFTR-mediated and modulated bicarbonate secretion in the pancreatic duct, including the role of the osmotic stress/chloride sensor WNK1 and the scaffolding protein IRBIT, and current knowledge about the role of CFTR in genetic and acquired forms of pancreatitis. Furthermore, we discuss the perspectives for CFTR modulator therapy in the treatment of exocrine pancreatic insufficiency and pancreatitis and introduce pancreatic organoids as a promising model system to study CFTR function in the human pancreas, its role in the pathology of pancreatitis and its sensitivity to CFTR modulators on a personalized basis.

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p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders?

Cited by 10 publications

References 22 publications

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Bicarbonate Transport in Cystic Fibrosis and Pancreatitis

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