Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome

Sheridan, Molly B.; Fong, Peter; Groman, Joshua D.; Conrad, Carol; Flume, Patrick A.; Díaz, Rubén; Harris, Christopher; Knowles, Michael R.; Cutting, Garry R.

doi:10.1093/hmg/ddi374

Cited by 76 publications

(55 citation statements)

References 18 publications

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“…Thus it may be argued that, by definition, a significant chloride secretory response was not going to be demonstrated. However, the rationale for restricting the study to this genotype was threefold: 1) evidence of sporadic function exists in the literature for patients with such genotypes [9][10][11], and our results also confirmed this (table 3); 2) studies have shown that homozygous DF508 genotype can be associated with long-term survival and this may be due to variation in CFTR function, not environmental influences [12,13]; and 3) increasingly the importance of ENaC and sodium transport on CF-like lung disease is being recognised [26]. This may also be directly relevant to CF, as differences in the level of interaction between ENaC and CFTR may explain differences in the expression of the disease and variability of survival.…”

Section: Discussionsupporting

confidence: 82%

Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function

Simmonds¹,

DʼSouza²,

Roughton³

et al. 2010

European Respiratory Journal

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Significant survival heterogeneity exists in cystic fibrosis. Our aim was to determine whether residual function of the cystic fibrosis transmembrane conductance regulator (CFTR) is present in long-term survivors with severe mutations.Nasal potential difference (PD) and sweat chloride were measured in 34 long-term survivors (aged o40 yrs) and compared with young patients (18-23 yrs) with severe (n530) and mild (n531)

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Section: Discussionsupporting

confidence: 82%

Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function

Simmonds¹,

DʼSouza²,

Roughton³

et al. 2010

European Respiratory Journal

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“…In addition, other genes either with or without a heterozygous CFTR genotype could produce the "nonclassic" CF phenotype in the absence of homozygous CFTR mutation as shown previously (Groman et al, 2002). Recently, it was shown that an ENaC gene (SCNN1) produced a non-classical CF phenotype (Sheridan et al, 2005) and ENaC was shown previously to be involved in stretch-induced muscle constriction (Jernigan and Drummond, 2005).…”

Section: Discussionmentioning

confidence: 78%

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Cohen

Larson

2006

Developmental Dynamics

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There is growing evidence for the role of CFTR (cystic fibrosis transmembrane conductance regulator) in lung development and differentiation. The mechanism by which the chloride channel could affect lung organogenesis, however, is unknown. In utero CFTR gene transfer in the fetal lungs of mice, rats, and non-human primates was shown previously to alter lung structure and function. A study of the genes altered in the fetal rat lung following CFTR overexpression was initiated in an effort to determine the molecular mechanism for CFTR-dependent differentiation. In utero gene transfer with recombinant adenoviruses carrying either a reporter gene or CFTR resulted in the increased expression of a number of genes upon microarray analysis. The majority of the genes overexpressed in the CFTR-treated lungs were primarily associated with muscle structure and function. Histological and biochemical characterization of these proteins including myosin heavy chain, heat shock protein 27, and isoforms of myosin light chain showed that CFTR overexpression had a profound effect on smooth muscle contraction-related proteins. The CFTR-dependent regulation of smooth muscle contraction related proteins was shown to be related to chloride and extracellular ATP and was dependent upon the PI3 Kinase and Phospholipase C pathways. The changes in smooth muscle proteins were consistent with CFTR-dependent contractions of the embryonic airway smooth muscle. An assay was developed using fluorescent polystyrene beads to show that CFTR did indeed increase amniotic fluid flow into the fetal lung. Increased amniotic fluid pressure was shown previously to be associated with stretch-induced differentiation of the lung. Evaluation of neonatal respiratory function showed that CFTR-dependent muscle contractions and increased amniotic fluid pressure resulted in accelerated maturation of the neonatal rat lung. In addition, these CFTR-dependent changes were shown to be sufficient to reverse the lung phenotype of the CFTR knockout mouse. Mechanical forces influence lung development through pulmonary distension. CFTR overexpression in the fetal lung altered differentiation and development in the lung. These results are consistent with CFTR influencing lung development by regulating the muscle contractions associated with cytoskeletal tension and stretch induced differentiation. Deficiency of CFTR altering lung development would contribute significantly to the Cystic Fibrosis disease phenotype.

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“…Moreover, the percentage of undetected mutations increases from northern to southern European populations. CFTR mutations may 34 However, the diagnostic utility of ENaC testing in routine practice has not been determined.…”

Section: Methods For Cftr Gene Analysismentioning

confidence: 99%

Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations

Dequeker

Stuhrmann

Morris³

et al. 2008

Eur J Hum Genet

208

160

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The increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

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Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome

Cited by 76 publications

References 18 publications

Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function

Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations

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