Variant Cystic Fibrosis Phenotypes in the Absence of<i>CFTR</i>Mutations

Groman, Joshua D.; Meyer, Michelle; Wilmott, Robert W.; Zeitlin, Pamela L.; Cutting, Garry R.

doi:10.1056/nejmoa011899

Cited by 153 publications

(108 citation statements)

References 24 publications

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“…Such a possible modifier gene was demonstrated in the mouse model (Haston et al, 2002). 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: 72%

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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Section: Discussionmentioning

confidence: 72%

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

Cohen

Larson

2006

Developmental Dynamics

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“…In cases where CFTR genotyping had not been performed or was incomplete, DNA samples were typed for 58 CFTR alleles using the Roche PCR-based Line Probe Assay (Roche Molecular Systems, Alameda, CA) (24). DNA samples with one or more unidentified CFTR mutations following typing with the Line Probe Assay were subjected to DNA sequencing of all coding regions of CFTR and flanking introns (25). For genome-wide linkage studies, patients were genotyped by the Marshfield Genotyping Center for 402 polymorphic short tandem repeat markers with an average spacing of 10 cM, or 7.5 Mb.…”

Section: Dna Isolation and Genotyping Methodsmentioning

confidence: 99%

Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

et al. 2006

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“…Although this series clearly suffers from ascertainment bias because most men were probably tested due to their symptoms, the data do reinforce the observations that many men with CBAVD have a genotype of one CF mutation and a 5T in trans. [23][24][25] We were unable to determine how many of these men were tested because of fertility problems versus population-based carrier screening. Chillon et al 23 described 3 adult males with CBAVD and lung disease who were compound heterozygotes for delta F508 and 5T.…”

Section: Clinical Significance Of 5tmentioning

confidence: 99%

“…[23][24][25] We were unable to determine how many of these men were tested because of fertility problems versus population-based carrier screening. Chillon et al 23 described 3 adult males with CBAVD and lung disease who were compound heterozygotes for delta F508 and 5T.…”

Section: Clinical Significance Of 5tmentioning

confidence: 99%

Cystic fibrosis screening: Lessons learned from the first 320,000 patients

Strom

Crossley

Redman

et al. 2004

Genetics in Medicine

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Variant Cystic Fibrosis Phenotypes in the Absence ofCFTRMutations

Abstract: Factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic cystic fibrosis caused by CFTR dysfunction.

Cited by 153 publications

References 24 publications

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

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

Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

Cystic fibrosis screening: Lessons learned from the first 320,000 patients

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