Mutations in CFTR associated with mild-disease-form CI- channels with altered pore properties

Sheppard, David N.; Rich, Devra P.; Ostedgaard, Lynda S.; Gregory, Richard J.; Smith, Alan E.; Welsh, Michael J.

doi:10.1038/362160a0

Cited by 452 publications

(390 citation statements)

References 24 publications

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“…Most of the class IV mutations analysed to date are located within the membrane-spanning domains. Expression of several such mutants in a heterologous system resulted in the production of a chloride current that was activated by cAMP (Sheppard et al 1993). Regulation by ATP appeared to be normal; however, the current was much reduced due to a decrease in amplitude of a singlechannel current and also a lower open state probability.…”

Section: Class III Mutations Affecting Cl − Channel Regulation/gatingmentioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

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SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

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Section: Class III Mutations Affecting Cl − Channel Regulation/gatingmentioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

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“…Class IV mutations alter the conductivity of the chloride channel in CFTR. In some cases, these mutations are intimate to the ion conduction pore of the CFTR channel (Sheppard et al 1993), whereas others appear to affect conductivity through allosteric mechanisms (Seibert et al 1996b). Class V mutations reduce the level of wildtype CFTR that is produced by splicing mutations.…”

Section: Different Classes Of Mutationsmentioning

confidence: 99%

“…Mutations that have a frequency in CF patients exceeding 1% have been investigated in a variety of expression systems for their effect on the splicing of CFTR RNA or the function of the CFTR protein (Cheng et al 1990;Gregory et al 1991;Sheppard et al 1993). Several dozen other mutations reported in patients have been investigated for their functional effects (e.g., Seibert et al 1996aSeibert et al , 1997.…”

mentioning

confidence: 99%

Assessing the Disease-Liability of Mutations in CFTR

Férec

Cutting

2012

Cold Spring Harbor Perspectives in Medicine

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“…The mutation R117H which accounts for approximately 0.8% of mutant alleles, changes an arginine to an histidine in a transmembrane domain of the protein, altering the conductance of the ion channel. 16 The IVS-8 polymorphism affects the splicing efficiency of intron 8. 17,18 A tract of 7T or 9T at the 3Ј end of intron 8 insures proper splicing of the intron while a 5T results in a majority of mRNA lacking exon 9.…”

mentioning

confidence: 99%

Long-Range (17.7 kb) Allele-Specific Polymerase Chain Reaction Method for Direct Haplotyping of R117H and IVS-8 Mutations of the Cystic Fibrosis Transmembrane Regulator Gene

Pont-Kingdon

Jama

Miller

et al. 2004

The Journal of Molecular Diagnostics

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Genotyping of genetic polymorphisms is widely used in clinical molecular laboratories to confirm or predict diseases due to single locus mutations. In contrast, very few molecular methods determine the phase or haplotype of two or more mutations that are kilobases apart. In this report, we describe a new method for haplotyping based on long-range allelespecific PCR. Reaction conditions were established to circumvent the incompatibility of using allele-specific primers and a polymerase with proofreading activity. Detection of locus single mutations affecting gene function has been very successful in providing molecular diagnostics for human genetic diseases. In contrast, detection of two or more mutations on the same gene and determination of their phase (or haplotype) is more challenging. Advances in the field of human genome mapping, 1 the search for complex disease determinants, 2 pharmacogenomics, 3 and accumulation of data from mutation screening programs 4 underline the need to develop additional molecular haplotyping methods. Current technologies require physical separation of chromosomes or cloning or are limited to analysis of single nucleotide polymorphism (SNPs) present in the range of 1 kilobase (kb). [5][6][7][8][9][10][11][12][13][14] One recent exception is the development of a long-range molecular technique using a twostep PCR/ligation procedure. 15 Here we describe an assay that uses long-range allele-specific amplification to haplotype two mutations separated by 17.7 kb in the cystic fibrosis transmembrane regulator (CFTR) gene.The CFTR gene encodes a chloride channel and mutations in this gene are responsible for classic cystic fibrosis (CF) and atypical forms of the disease. Two of these mutations, R117H in exon 4 and the 5T polymorphism of the polythymidine tract in intron 8 (IVS-8 5T polymorphism) have a phenotypic synergic effect. The mutation R117H which accounts for approximately 0.8% of mutant alleles, changes an arginine to an histidine in a transmembrane domain of the protein, altering the conductance of the ion channel. 16 The IVS-8 polymorphism affects the splicing efficiency of intron 8. 17,18 A tract of 7T or 9T at the 3Ј end of intron 8 insures proper splicing of the intron while a 5T results in a majority of mRNA lacking exon 9. 19 -22 Each mutation is independently considered mild because in both cases, residual activity of the ion channel remains. Therefore, an individual carrying the R117H mutation and the IVS-8 5T polymorphism on two different chromosomes (in trans) is not affected by, nor considered a carrier of classic CF 23 although this individual might present with atypical CF. In contrast, a gene with both R117H and IVS-8 5T (in cis) is severely affected. 24 Both R117H and the IVS-8 5T variants have been found at higher frequencies in individuals with atypical CF than in the normal population. 22,[25][26][27] If an individual is heterozygous for both R117H and the IVS-8 5T variant, it is necessary to establish if both mutations are in cis or in trans to correctly analy...

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Mutations in CFTR associated with mild-disease-form CI- channels with altered pore properties

Cited by 452 publications

References 24 publications

The Phenotypic Consequences of CFTR Mutations

The Phenotypic Consequences of CFTR Mutations

Assessing the Disease-Liability of Mutations in CFTR

Long-Range (17.7 kb) Allele-Specific Polymerase Chain Reaction Method for Direct Haplotyping of R117H and IVS-8 Mutations of the Cystic Fibrosis Transmembrane Regulator Gene

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