Since the 1960s, CF has been one of the most publicly visible of all human monogenic diseases. It is the most common autosomal recessive genetic disorder of children in populations of European ancestry in the United States, with an incidence of ~1 in 2500 births (and thus a carrier frequency of ~1 in 25), whereas it is much less prevalent in other population groups, such as Blacks (1 in 15,000 births) and Asians (1 in 31,000 births). The isolation of the CF gene (called CFTR, for CF transmembrane regulator) more than 30 years ago was one of the first illustrations of the power of molecular genetic and genomic approaches to identify disease genes. Physiologic analyses have shown that the CFTR protein is a regulated chloride channel located in the apical mem brane of the epithelial cells affected by the disease.

The Phenotypic Features of Cystic Fibrosis. The lungs and exocrine pancreas are the principal organs affected by CF, but a major diagnostic feature is increased sweat sodium and chloride concentrations (often first noted when parents kiss their infant). CF is most commonly identified by newborn screening in regions of the world where that is offered. Elsewhere, in most CF patients, the diagnosis is initially based on the clinical pulmonary or pancreatic findings and on an elevated level of sweat chloride. less than 2% of patients have normal sweat chloride concentration despite an otherwise typical clinical picture; in these cases, molecular analysis can be used to ascertain whether they have pathogenic variants in the CFTR gene.

The pancreatic defect in CF is a maldigestion syn drome due to the deficient excretion of pancreatic enzymes (lipase, trypsin, chymotrypsin). Approximately 5% to 15% of patients with CF have enough residual pancreatic exocrine function for normal digestion and are designated “pancreatic sufficient.” Moreover, patients with CF who are pancreatic sufficient have better growth and overall prognosis than the majority, who are “pancreatic insufficient.” The clinical heterogeneity of the pancreatic disease is at least partly due to allelic heterogeneity, as discussed later.

Many other features are observed in CF patients. For example, neonatal lower intestinal tract obstruction (meconium ileus) occurs in 10% to 15% of CF newborns. The genital tract is also affected; females with CF have some reduction in fertility, but more than 98% of males with CF are infertile because they lack the vas deferens, a phenotype known as congenital bilateral absence of the vas deferens (CBAVD). In a striking example of allelic heterogeneity giving rise to a partial phenotype, it has been found that some infertile males who are otherwise well (i.e., have no pulmonary or pancreatic disease) have CBAVD associated with specific variants in the CFTR gene. Similarly, some individuals with idiopathic chronic pancreatitis are carriers of variants in CFTR yet lack other clinical signs of CF.

The CFTR Gene and Protein. The CFTR gene has 27 exons and spans ~190 kb of DNA. The CFTR protein encodes a large integral membrane protein of ~170 kD (Fig. 1). The protein belongs to the ABC (ATP [adenosine triphosphate]–binding cassette) family of trans port proteins. At least 27 ABC transporters have been implicated in mendelian disorders and complex trait phenotypes.

Fig1. The structure of the CFTR gene and a schematic of the CFTR protein. Selected variants are shown. The exons, introns, and domains of the protein are not drawn to scale. Phe508del 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. (Based on Zielinski J: Genotype and phenotype in cystic fibrosis, Respiration 67:117–133, 2000.)

The CFTR chloride channel has five domains, shown in Fig. 1: 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 variants in each of them (see Fig. 1). 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. CF is due to abnormal fluid and electrolyte transport across epithelial apical membranes. This abnormality leads to disease in the lung, pancreas, intestine, hepatobiliary tree, and male genital tract. The physiologic abnormalities have been most clearly elucidated for the sweat gland. The loss of CFTR function means that chloride in the duct of the sweat gland cannot be reabsorbed, leading to a reduction in the electrochemical gradient that normally drives sodium entry across the apical membrane. This defect leads, in turn, to the increased chloride and sodium concentrations in sweat. The effects on electrolyte transport due to the abnormalities in the CFTR protein have also been carefully studied in airway and pancreatic epithelia. In the lung, the hyperabsorption of sodium and reduced chloride secretion result in a depletion of airway surface liquid. Consequently, the mucous layer of the lung may become adherent to cell surfaces, disrupting the cough and cilia-dependent clearance of mucus and providing a niche favorable to Pseudomonas aeruginosa, the major cause of chronic pulmonary infection in CF.

The Genetics of Cystic Fibrosis

Pathogenic Variants in the Cystic Fibrosis Trans membrane Regulator Polypeptide. The most common CF pathogenic variant is a deletion of a phenylalanine residue at position 508 (p.Phe508del, shortened to F508del) in the first ATP-binding fold (NBD1; see Fig. 1), accounting for ~70% of all CF alleles in populations of European ancestry. In these populations, only seven other pathogenic variants are more frequent than 0.5%, and the remainder are each quite rare. Variants of all types have been identified, but the largest single group (nearly half) are missense substitutions. The remainder are point variants of other types, and less than 1% are genomic rearrangements. Although nearly 2000 CFTR gene sequence variants have been associated with disease, the actual number of missense variants that are disease-causing is uncertain because few have been subjected to functional analysis. However, a project called the Clinical and Functional Translation of CFTR (CFTR2 project; cftr2.org) has succeeded in assigning pathogenicity to more than 466 CFTR variants (including 174 missense variants and in frame deletions), which together account for at least 96% of all CFTR alleles worldwide.

Although the specific biochemical abnormalities associated with most CF alleles 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 Fig. 1.

• Class 1 variants are null alleles – no CFTR poly peptide is produced. This class includes alleles with premature stop codons or those 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 variants impair the folding of the CFTR protein, thereby arresting its maturation. The F508del variant typifies this class; this misfolded protein can not exit from the endoplasmic reticulum. However, the biochemical phenotype of the F508del protein is complex because it also exhibits defects in stability and activation in addition to impaired folding.

• Class 3 variants allow normal delivery of the CFTR protein to the cell surface but disrupt its function (see Fig. 1). The prime example is the p.Gly551Asp variant that impedes the opening and closing of the CFTR ion channel at the cell surface.

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

• Class 5 variants reduce the number of CFTR transcripts.

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

A Cystic Fibrosis Genocopy: Pathogenic Variants in the Epithelial Sodium Channel Gene SCNN1. Although CFTR is the only gene that has been associated with classic CF, several families with nonclassic presentations (including CF-like pulmonary infections, less severe intestinal disease, elevated sweat chloride levels) have been found to carry pathogenic variants in the epithelial sodium channel gene SCNN1, a genocopy, that is, a phenotype that, although genetically distinct, has a very closely related phenotype. This finding is consistent with the functional interaction between the CFTR protein and the epithelial sodium channel. Its main clinical significance, at present, is the demonstration that patients with nonclassic CF display locus heterogeneity and that if CFTR pathogenic variants are not identified in a particular case, abnormalities in SCNN1 must be considered.

Genotype-Phenotype Correlations in Cystic Fibrosis. Because all patients with the classic form of CF appear to have pathogenic variants in the CFTR gene, clinical heterogeneity in CF must arise from allelic heterogeneity, from the effects of other modifying loci, or from nongenetic factors. Independent of the CFTR alleles that a particular patient may have, a significant genetic contribution from other (modifier) genes to several CF phenotypes has been recognized, with effects on lung function, neonatal intestinal obstruction, and diabetes.

Two generalizations have emerged from the genetic and clinical analysis of patients with CF. First, the specific CFTR genotype is a good predictor of exocrine pancreatic function. For example, patients homozygous for the common F508del variant or for predicted null alleles generally have pancreatic insufficiency. On the other hand, alleles that allow the synthesis of a partially functional CFTR protein, such as Arg117His (see Fig. 1), tend to be associated with pancreatic sufficiency.

Second, however, the specific CFTR genotype is a poor predictor of the severity of pulmonary disease. For example, among patients homozygous for the F508del variant, the severity of lung disease is variable. One reason for this poor phenotype-genotype correlation is inherited variation in the gene encoding transforming growth factor β1 (TGFβ1), as also dis cussed in Chapter 9. Overall, the evidence indicates that TGFB1 alleles that increase TGFβ1 expression lead to more severe CF lung disease, perhaps by modulating tissue remodeling and inflammatory responses. Other genetic modifiers of CF lung disease, including alleles of the interferon-related developmental regulator 1 gene (IFRD1) and the interleukin-8 gene (IL8), may act by influencing the ability of the CF lung to tolerate infection. Similarly, a few modifier genes have been identified for other CF-related phenotypes, including diabetes, liver disease, and meconium ileus.

The Cystic Fibrosis Gene in Populations. At present, it is not possible to account for the high frequency of disease-causing CFTR alleles (about 1 in 25) among populations of European descent. The disease is much less frequent in others, although it has been reported in those of Indigenous, African, and Asian descent (e.g., ~1 in 90,000 Hawaiians of Asian descent). The F508del allele is the only one found to date that is common in virtually all populations of European ancestry, but its frequency among all pathogenic alleles varies significantly in different European populations, from 88% in Denmark to 45% in southern Italy.

In populations in which the F508del allele frequency is ~70% of all mutant alleles, ~50% of patients are homozygous for the F508del allele; an additional 40% are genetic compounds for F508del and another mutant allele. In addition, ~70% of CF carriers have the F508del variant. As noted earlier, except for F508del, other variants at the CFTR locus are rare, although in specific populations some alleles are relatively common.

Population Screening. Both carrier screening and newborn screening for CF is offered universally in the United States, Canada, Australia, New Zealand, most of western Europe, Russia, Brazil, Argentina, and Chile.

Genetic Analysis of Families of Patients and Prenatal Diagnosis. The high frequency of the F508del allele is useful when CF patients without a family history present for DNA diagnosis. The identification of the F508del allele, in combination with a panel of 127 common variants suggested by the American College of Medical Genetics and Genomics, can be used to predict the status of family members for confirmation of dis ease (e.g., in a newborn or a sibling with an ambiguous presentation), carrier detection, and prenatal diagnosis. Given the vast knowledge of CFTR variants in many populations, direct variant detection is the method of choice for genetic analysis. For couples with a 25% risk, preimplantation genetic testing following in vitro fertilization can be offered; alternatively, for fetuses with a 1 in 4 risk, prenatal diagnosis by DNA analysis at 10 to 12 weeks, with tissue obtained by chorionic villus biopsy, is the method of choice.

Molecular Genetics and the Treatment of Cystic Fibrosis. Historically, the treatment of CF has been directed toward controlling pulmonary infection and improving nutrition. Increasing knowledge of the molecular pathogenesis has made it possible to design pharmacologic interventions that modulate CFTR function in most patients. Alternatively, gene transfer therapy may be possible in the future for CF, but there are many difficulties.

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مواضيع ذات صلة

Familial Hypercholesterolemia: A Genetic Hyperlipidemia

A Loss of Glycosylation: Mucolipidosis II or I-Cell Disease

Congenital Disorders of Glycosylation

The Example of Diseases Related to the X Chromosome: Hemophilia A and B

The Example of an Autosomal Recessive Disease: Cystic Fibrosis

Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The β- Thalassemias

The α- Thalassemias

Hemoglobin Structural Alterations

Transient neonatal diabetes

Permanent neonatal diabetes

Fragile X Syndrome