Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.

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Identification of the cystic fibrosis gene: genetic analysis.

An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.

https://science.sciencemag.org/content/sci/245/4922/1059.full.pdf

Identification of the cystic fibrosis gene: Chromosome walking and jumping

https://www.cell.com/cell/pdf/0092-8674(93)90353-R.pdf

Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis

The diagnosis of cystic fibrosis: A consensus statement☆☆☆★★★

In his book "Analysis of Human Genetic Linkage" Jurg Ott laid out the principles by which geneticists perform studies of genetic linkage in humans. Here, in the "Handbook of Human Genetic Linkage", Joseph Terwilliger and Jurg Ott provide a companion piece to the previous work, showing how its principles may be applied in practice. "Handbook of Human Genetic Linkage" contains detailed instructions on how to carry out linkage analysis, guiding the reader through each process on a step-by-step basis. The chapters are grouped into three main sections: two-point linkage analysis, multi-point linkage analysis, and such advanced topics as mutation rates, gene frequencies, linkage disequilibrium, complex diseases and computer simulation. Each chapter ends with exercises that can be performed on an IBM PC-compatible computer. The solutions are supplied at the end of each section.

/pdf/handbook-of-human-genetic-linkage-18y77nlre0.pdf

Handbook of Human Genetic Linkage

We showed elsewhere that the pancreatic function status of cystic fibrosis (CF) patients could be correlated to mutations in the CF transmembrane conductance regulator (CFTR) gene. Although the majority of CF mutations--including the most common, delta F508--strongly correlated with pancreatic insufficiency (PI), approximately 10% of the mutant alleles may confer pancreatic sufficiency (PS). To extend this observation, genomic DNA of 538 CF patients with well-documented pancreatic function status were analyzed for a series of known mutations in their CFTR genes. Only 20 of the 25 mutations tested were found in this population. They accounted for 84% of the CF chromosomes, with delta F508 being the most frequent (71%), and the other mutations accounted for less than 5% each. A total of 30 different, complete genotypes could be determined in 394 (73%) of the patients. The data showed that each genotype was associated only with PI or only with PS, but not with both. This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T, 1717-1G----A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T.

/pdf/genetic-determination-of-exocrine-pancreatic-function-in-4y34wyuv9a.pdf

Genetic determination of exocrine pancreatic function in cystic fibrosis.

Patients with cystic fibrosis (CF) generally suffer from chronic obstructive lung disease, pancreatic insufficiency (PI), and a number of other exocrine malfunctions. Approximately 15% of CF patients are, however, pancreatic sufficient. To investigate whether the two clinical subgroups, PI and pancreatic sufficiency (PS), are caused by different CF mutant alleles, we have performed linkage disequilibrium and haplotype association analysis with three DNA markers that are tightly linked to the CF locus. The study showed that the allelic and haplotype distributions for these RFLPs are significantly different between the two groups. The data suggest that most of the CF-PI patients are probably descendants of a single mutational event at the CF locus and that the CF-PS patients resulted from multiple, different mutations. While final interpretation of these data awaits molecular cloning of the CF gene, the information on haplotype association in CF may be useful in genetic counseling and disease prognosis, in identifying the gene itself, and in defining the mutations.

/pdf/dna-marker-haplotype-association-with-pancreatic-sufficiency-3flubr5h81.pdf

DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis.

Obstructive azoospermia due to congenital absence of vas deferens is a prominent clinical feature among male patients with cystic fibrosis (CF). A similar autosomal recessive condition with no other CF manifestations is classified as congenital bilateral absence of vas deferens (CBAVD). Since 50%-64% of CBAVD patients have been found to be positive for at least one known CFTR mutation, it is believed that at least part of the CBAVD population represents an atypical form of CF affecting only the male reproductive system. This explanation is not completely satisfactory, however, because only {approximately}10% of CBAVD patients are found to carry known CF mutations on both chromosomes, even after exhaustive screening of the entire CFTR coding region. Here we present data to show that a previously known sequence variant in intron 8 of the CFTR gene is a specific and frequent mutation associated with CBAVD. 20 refs., 1 tab.

Mary Corey

Papers

Genetic determination of exocrine pancreatic function in cystic fibrosis.

DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis.

CFTR gene variant for patients with congenital absence of vas deferens.

Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis

Prevalence of vitamin K deficiency in cystic fibrosis