Figure 12-15 The structure of the CFTR gene and a schematic of the CFTR protein. Selected mutations are shown. The exons, introns, and domains of the protein are not drawn to scale. ΔF508 results from the deletion of TCT or CTT, replacing the Ile codon with ATT, and deleting the Phe codon. CF, Cystic fibrosis; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; R-domain, regulatory domain. See Sources & Acknowledgments.

The CFTR chloride channel has five domains, shown in Figure 12-15: two membrane-spanning domains, each with six transmembrane sequences; two nucleotide (ATP)-binding domains; and a regulatory domain with multiple phosphorylation sites. The importance of each domain is demonstrated by the identification of CF-causing missense mutations in each of them (see Fig. 12-15). The pore of the chloride channel is formed by the 12 transmembrane segments. ATP is bound and hydrolyzed by the nucleotide-binding domains, and the energy released is used to open and close the channel. Regulation of the channel is mediated, at least in part, by phosphorylation of the regulatory domain.

The Pathophysiology of Cystic Fibrosis.

The Genetics of Cystic Fibrosis

Mutations in the Cystic Fibrosis Transmembrane Regulator Polypeptide.

Although the specific biochemical abnormalities associated with most CF mutations are not known, six general classes of dysfunction of the CFTR protein have been identified to date. Alleles representative of each class are shown in Figure 12-15.

Class 1 mutations are null alleles—no CFTR polypeptide is produced. This class includes alleles with premature stop codons or that generate highly unstable RNAs. Because CFTR is a glycosylated membrane-spanning protein, it must be processed in the endoplasmic reticulum and Golgi apparatus to be glycosylated and secreted.

Class 2 mutations impair the folding of the CFTR protein, thereby arresting its maturation. The ΔF508 mutant typifies this class; this misfolded protein cannot exit from the endoplasmic reticulum. However, the biochemical phenotype of the ΔF508 protein is complex, because it also exhibits defects in stability and activation in addition to impaired folding.

Class 3 mutations allow normal delivery of the CFTR protein to the cell surface, but disrupt its function (see Fig. 12-15). The prime example is the Gly551Asp mutation that impedes the opening and closing of the CFTR ion channel at the cell surface. This mutation is particularly notable because, although it constitutes only approximately 2% of CFTR alleles, the drug ivacaftor has been shown to be remarkably effective in correcting the function of the mutant Gly551Asp protein at the cell surface, resulting in both physiological and clinical improvements (see Chapter 13).

Class 4 mutations are located in the membrane-spanning domains and, consistent with this localization, have defective chloride ion conduction.

Class 5 mutations reduce the number of CFTR transcripts.

Class 6 mutant proteins are synthesized normally but are unstable at the cell surface.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Defects

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