The Clinical Biology of Cystic Fibrosis Transmembrane Regulator Protein: Its Role and Function in Extrapulmonary Disease

Abstract

Normal cystic fibrosis (CF) transmembrane regulator (CFTR) protein has multiple functions in health and disease. Many mutations in the CFTR gene produce abnormal or absent protein. CFTR protein dysfunction underlies the classic CF phenotype of progressive pulmonary and GI pathology but may underlie diseases not usually associated with CF. This review highlights selected extrapulmonary disease that may be associated with abnormal CFTR. Increasing survival in CF is associated with increasing incidence of diseases associated with aging. CFTR dysfunction in older individuals may have novel effects on glucose metabolism, control of insulin release, regulation of circadian rhythm, and cancer cell pathophysiology. In individuals who have cancers with acquired CFTR suppression, their tumors may more likely exhibit rapid expansion, epithelial-to-mesenchymal transformation, abnormally reduced apoptosis, and increased metastatic potential. The new modulators of CFTR protein synthesis could facilitate the additional exploration needed to better understand the unfolding clinical biology of CFTR in human disease, even as they revolutionize treatment of patients with CF.

Keywords: cancer; circadian rhythm; cystic fibrosis transmembrane regulator; hypoglycemia; sleep.

Figure 1

Causal inference diagram of cystic fibrosis clinical disease. Disease begins with allelic homozygosity of cystic fibrosis transmembrane regulator mutations and leads directly to abnormal secretions. Organ-specific disease ensues, directly affecting the lung, sinuses, pancreas, liver, and reproductive organs. Inflammation associated with airway infections and recurrent acute exacerbations of disease drive and are driven by worsening lung function. Factors intrinsic to patients such as age and sex alter the effects of cystic fibrosis on lung disease and survival. Malnutrition as a result of pancreatic and liver involvement affects the attainment of adult height and weight, and all three affect lung function and survival., Sinusitis and infertility do not lead to decreased survival but cause substantial worsening of quality of life, as do other manifestations of disease., , Various complications of disease include diabetes, which contributes to early death. Treatments such as lung transplantation and liver transplantation markedly change disease and treatment profiles and have effects that alter survival.

Figure 2

Cystic fibrosis transmembrane regulator (CFTR) protein. CFTR protein consists of a 1480 amino acid chain. Starting from the amine end, there is a Lasso motif, a membrane-spanning domain (amino acids [AA] 70-376) with an associated nucleotide-binding domain (AA 391-644), a regulatory domain (AA 654-838), another membrane-spanning domain (AA 841-1175), another nucleotide-binding domain (AA 1203-1437) and a final threonine-arginine-leucine tail at the carboxyl end. The two similar membrane-spanning domains work together to transport anions; the two similar nucleotide-binding domains mediate adenosine triphosphate hydrolysis, and opening and closing of the actual anion channel; and a threonine-arginine-leucine carboxyl terminal anchors the protein to the cytoskeleton and mediates interactions with other proteins in the cell. The three most common alleles are shown for most of the six categories of mutations. Arrows from each mutation name point to the approximate regions in the full protein that are affected in the underlying DNA sequence mutation as indicated by either the legacy amino acid or modern nucleotide-based mutation nomenclatures. The most common allele world-wide is F508del, a class II gene mutation. Mutation class is associated with degree of clinical severity, and common mutations occurring following the regulatory domain, AA 838, are associated with preservation of CFTR-associated bicarbonate transport and pancreatic sufficiency. A regularly updated list of CFTR variants, allele frequencies, and disease-causing potential is available at www.cftr2.org, the source for the mutations noted in the figure. Details regarding mutation classifications have been reviewed and are available as published.,

Figure 3

Involvement of CFTR protein in hypoglycemia-sensing neurons. When circulating G levels drop (lower left), fewer molecules are transported by GLUT4 G-conducting channels into hypothalamic neurons specialized to respond to hypoglycemia., , These neurons are located in a portion of the brain that has exposure to circulating G levels. The decreased G levels trigger an increase in synthesis of NPY and AgRP. AMP levels rise while ATP levels drop, triggering an increase in AMPK activity., AMPK activity is amplified by a positive feedback cycle involving phosphorylation of nNOS, an increase in NO that binds SGC, which causes an increase in cyclic guanosine monophosphate that positively feeds back on AMPK. Increased AMPK blocks the action of CFTR protein, resulting in depolarization of the neuron which releases NPY and AgRP. Both peptides counter hypoglycemia by increasing appetite. CFTR protein dysfunction prevents normal depolarization and the release of NPY and AgRP, a mechanism consistent with the clinical observation that children with cystic fibrosis do not respond appropriately to hypoglycemia. AgRP = agouti-related peptide; AMP = adenosine monophosphate; AMPK = adenosine monophosphate-kinase; ATP = adenosine triphosphate; G = glucose; GLUT4 = glucose transporter type 4; nNOS = neuronal nitric oxide synthase; NO = nitric oxide; NPY = neuropeptide Y; SGC = soluble guanylyl cyclase. See Figure 2 legend for expansion of other abbreviation.