Dataset Information

The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

ABSTRACT: Congenital chloride diarrhea (CLD) is characterized by watery stools with high chloride content beginning prenatally and is inherited as an autosomal recessive trait. Perfusion studies have established a basic defect in ileal and colonic Cl-/HCO3- transport, resulting in defective chloride absorption. The protein and its gene defects have, however, remained uncharacterized. We attempted to exclude candidate genes by considering linkage disequilibrium as well as genetic linkage in a small number of Finnish families. Initial results were suggestive of linkage between CLD and the cystic fibrosis transmembrane regulator gene (CFTR). Extended analysis in eight families confirmed close linkage to chromosome 7 markers proximal of CFTR, with maximum logarithm of odds scores of 5.11 and 5.06 for D7S501 and D7S496, respectively, at zero recombination. Allelic associations were observed that were striking between CLD and D7S496 and weaker between CLD and D7S501. Multipoint analyses mapped CLD unequivocally at D7S496 with a maximum logarithm of odds score of 9.33. We conclude that the CLD gene maps close to, but is distinct from, CFTR.

SUBMITTER: Kere J

PROVIDER: S-EPMC47842 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

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The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Kere J J Sistonen P P Holmberg C C de la Chapelle A A

Proceedings of the National Academy of Sciences of the United States of America 19931101 22

Congenital chloride diarrhea (CLD) is characterized by watery stools with high chloride content beginning prenatally and is inherited as an autosomal recessive trait. Perfusion studies have established a basic defect in ileal and colonic Cl-/HCO3- transport, resulting in defective chloride absorption. The protein and its gene defects have, however, remained uncharacterized. We attempted to exclude candidate genes by considering linkage disequilibrium as well as genetic linkage in a small number ...[more]

PMID: 7504277

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Project description:Background: Most cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to protein misfolding and degradation by the ubiquitin-proteasome system. Previous studies demonstrated that PIAS4 facilitates the modification of wild-type (WT) and F508del CFTR by small ubiquitin-like modifier (SUMO)-1, enhancing CFTR biogenesis by slowing immature CFTR degradation and producing increased immature CFTR band B. Methods: We evaluated two correction strategies using misfolding mutants, including the common variant, F508del. We examined the effects on mutant expression of co-expression with PIAS4 (E3 SUMO ligase), and/or the corrector, C18. To study the impact of these correction conditions, we transfected CFBE410- cells, a bronchial epithelial cell line, with a CFTR mutant plus: (1) empty vector, (2) empty vector plus overnight 5 μM C18, (3) PIAS4, and (4) PIAS4 plus C18. We assessed expression at steady state by immunoblot of CFTR band B, and if present, band C, and the corresponding C:B band ratio. The large PIAS4-induced increase in band B expression allowed us to ask whether C18 could act on the now abundant immature protein to enhance correction above the control level, as reported by the C:B ratio. Results: The data fell into three mutant CFTR categories as follows: (1) intransigent: no observable band C under any condition (i.e., C:B = 0); (2) throughput responsive: a C:B ratio less than control, but suggesting that the increased band C resulted from PIAS4-induced increases in band B production; and (3) folding responsive: a C:B ratio greater than control, reflecting C18-induced folding greater than that expected from increased throughput due to the PIAS4-induced band B level. Conclusion: These results suggest that the immature forms of CFTR folding intermediates occupy different loci within the energetic/kinetic folding landscape of CFTR. The evaluation of their properties could assist in the development of correctors that can target the more difficult-to-fold mutant conformations that occupy different sites within the CFTR folding pathway.

Dataset Information

The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Publications

The gene for congenital chloride diarrhea maps close to but is distinct from the gene for cystic fibrosis transmembrane conductance regulator.

Similar Datasets

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