Altered protein folding may be the molecular basis of most cases of cystic fibrosis philip j. Pedersen department of biological chendshy, the johns hopkins university, school of medicine, 725 north walfe street, baltimore, md 21205. More than 800 different mutations in the cftr cystic fibrosis transmembrane conductance regulator gene have been identified in cystic fibrosis cf patients. The cystic fibrosis transmembrane regulator cftr gene encodes an ion channel transporter, the cftr protein. Cystic fibrosis transmembrane conductance regulator cftr is a membrane protein and chloride channel in vertebrates that is encoded by the cftr gene the cftr gene codes for an abc transporterclass ion channel protein that conducts chloride ions across epithelial cell membranes. Mutations in the cftr gene lead to the production of a misfolded cftr protein which cannot be transported properly to the cell surface or is nonfunctional when it. Emergent properties of proteostasis in managing cystic fibrosis. Nov 21, 2016 cystic fibrosis cf is an inherited rare disorder that has no known cure. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Cftr, basic ion transport defects and cystic fibrosis lung disease.
The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Cystic fibrosis cf and approaches to alleviate the cf clinical phenotype. The product of this gene is a plasma membrane campdependent cl channel gated in response to binding and hydrolysis of atp4, 5, 6, 7. F508 in the cf transmembrane conductance regulator cftr, an ion channel 46. Metaminer cystic fibrosis cf represents a version of genegos metadiscovery suite that is enriched with content specificfor cystic fibrosis. The channel transports negatively charged particles called chloride ions into and out of cells. Cystic fibrosis transmembrane conductance regulator wikipedia. The gene defect was first described 25 years ago and much progress has been made since then in our understanding of how cftr mutations cause disease and how this can be addressed therapeutically. Cystic fibrosis is the most common lethal genetic disease in white populations. Cystic fibrosis cf is a generalized disorder of the secretory epithelia of all exocrine glands quinton 1990. Proteinfolding chaperones have both positive and negative. Quantitative proteomics reveals an altered cystic fibrosis.
Cystic fibrosis cf is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. A posttranslational modification code for cftr maturation is. The membrane protein, cystic fibrosis transmembrane conductance regulator cftr, functions as an ion channel. Cystic fibrosis as a disease of misprocessing of the. The cftr protein consists of a modular structure composed of two membrane. Alterations in epithelial secretions and mucociliary clearance contribute to chronic bacterial infection in cystic fibrosis cf lung disease, but whether cf lungs are unchanged in the absence of infection remains controversial. Cystic fibrosis as a disease of misprocessing of the cystic fibrosis transmembrane conductance regulator glycoprotein. The most 1 prevalent mutation in cf patients is a deletion of phe 508. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. Most mutant nascent chains do not pass quality control in the er.
The cftr gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. Cystic fibrosis cf remains the most common fatal hereditary lung disease. F508, impairs cftr folding and, consequently, its biosynthetic and. In an effort to further prolong the life span of patients with cf, many candidate therapies are being actively investigated. Pancreatitis and pancreatic cystosis in cystic fibrosis a.
Cystic fibrosis as a disease of misprocessing of the cystic. Deletion of phenylalanine508 phe508 from the nterminal nucleotidebinding domain nbd1 of the cystic fibrosis transmembrane conductance regulator cftr, a member of the atpbinding cassette abc transporter family, disrupts both its folding and function and causes most cystic fibrosis. The majority of mutations cause a severe cf phenotype, and people with this condition will require a wide variety of medical interventions and therapies. Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The major cause of morbidity and mortality in cf is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue. Cystic fibrosis cf, the most common lifeshortening autosomal recessive disorder in populations of european origin, is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene on chromosome 7. Cystic fibrosis cf is the most common lifethreatening monogenic disease a.
Mutations of the cftr gene lead to either misfolding and consequent degradation or dysfunctionaltered expression of the cftr protein or can. Altered equilibria among competing folding pathways may account for the primary effect of the phe508 deletion on nbd1 and may explain the failure of the whole multidomain protein to reach its native global configuration. Cystic fibrosis transmembrane conductance regulator. The cystic fibrosis transmembrane conductance regulator. Pdf cystic fibrosis a multiorgan protein misfolding disease. Cystic fibrosis occurs when the cystic fibrosis transmembrane conductance regulator cftr protein is either not made correctly, or not made at all. Cystic fibrosis cf is a chronic disease that affects 30,000 americans. In utero and postnatal vx770 administration rescues multiorgan disease in a ferret model of cystic. Lumacaftorivacaftor in patients with cystic fibrosis homozygous for phe508del cftr. Codon bias and the folding dynamics of the cystic fibrosis transmembrane. Altered protein folding may be the molecular basis of most. Mar 04, 2008 deletion of phenylalanine508 phe508 from the nterminal nucleotidebinding domain nbd1 of the cystic fibrosis transmembrane conductance regulator cftr, a member of the atpbinding cassette abc transporter family, disrupts both its folding and function and causes most cystic fibrosis.
Cftr biosynthesis alter the proteins interactions with. F508 mutation in the first nucleotide binding domain nbd1 alters the ability of the domain to fold into a functional threedimensional structure, providing a molecular. These include cystic fibrosis and other devastating diseases of childhood as well as alzheimers, parkinsons and other. The majority of mutations cause a severe cf phenotype, and people with this condition will require. Basics of the cftr protein cystic fibrosis foundation. Ooi b a emory university school of medicinechildrens healthcare of atlanta, 2015 uppergate dr.
Mild mutations are associated with a milder disease severity. Although cf is a complex multiorgan disease, morbidity and mortality are mainly determined by chronic. Cystic fibrosis cf is a disease caused by aberrant expression, or misfolding, of cftr. Quantitative proteomics reveals an altered cystic fibrosis in. Hutt1, jiansong tong1, marion bouchecareilh1, ning wang2. The manifestations of the disease are influenced not only by the type of mutation but also the. Cf is diagnosed by elevated electrolyte concentrations in sweat, reduced ion permeability. The most common causative mutation in cystic fibrosis is deletion of a phenylalanine residue at position 508. In addition cftr has a regulatory role over other ion channels in the cell membrane. The most common mutation, deletion of phenylalanine 508.
Pdf cystic fibrosis cf is a heterogeneous multiorgan disease caused by mutations in the cftr gene. This genetic disease of autosomal recessive inheritance is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene. Dec 18, 2003 several sporadic and genetic diseases are caused by protein misfolding. The most common mutation is the deletion of phenylalanine from the position508 f508delcftr, resulting in a misfoldedcftr protein, which is unable to fold, traffic and retain its plasma. However, cftr modulators are not available to all people with cf and better modulators are required to prevent disease progression. In 1985, the median predicted survival was 25 years of age, while in 2017, it had increased to 46 years. Mechanisms of proteinfolding diseases at a glance disease. The most common mutation is the deletion of phenylalanine from the position508 f508delcftr, resulting in a misfoldedcftr protein, which is unable to fold, traffic and retain its plasma membrane pm.
Cystic fibrosis cf is a recessive disorder caused by mutations to the gene encoding the cystic fibrosis transmembrane conductance regulator cftr, a chloride channel responsible for directing the movement of salt and water in and out of cells. Cystic fibrosis is an inherited disease that severely impairs the function of lungs and other organs. The treatment of cystic fibrosis cf has been transformed by orallybioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator cftr, which restore function to cf mutants. Alteration of the cystic fibrosis transmembrane conductance. Cftr functions as a cyclic adenosine monophosphatedependent anion channel that transports chloride and bicarbonate across epithelial surfaces, and disruption of these ion. Longterm issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Cystic fibrosis cf is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator, cftr.
Cystic fibrosis a multiorgan protein misfolding disease. Apr 27, 2017 study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use. F508, impairs cftr folding and, consequently, its biosynthetic and endocytic processing as well. Cystic fibrosis is an autosomal recessive, monogenetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene. Folded proteins were analyzed on a macrosphere gpc 300 7u gel. Af508 mutation in the first nucleotide binding domain nbd1 alters the ability of the domain to fold into a functional.
Cystic fibrosis cf, a fatal autosomal recessive genetic disease that affects over 60,000 people worldwide, is. A canonical example is provided by the disease cystic fibrosis, which is caused by mutations in cystic fibrosis transmembrane conductance regulator cftr, a plasma membrane chloride channel. Ne, atlanta, ga 30322, united states b school of womens and childrens health, medicine, university of new south wales and sydney childrens hospital randwick, sydney, australia. Altered protein folding may be the molecular basis of most cases of cystic fibrosis. Several sporadic and genetic diseases are caused by protein misfolding. Many genetic mutations have been associated with cf, but the impact of these mutations can be classified class ivi by how they affect the expression, or folding of, cftr. Pancreatitis and pancreatic cystosis in cystic fibrosis. A proteomic comparison of airway secretions from subjects with cf and control subjects shows alterations in key biological processes, including.
Protein folding chaperones have both positive and negative roles to play in cystic fibrosis research update aug. Genetics and molecular pathology of cystic fibrosis. Protein folding disease an overview sciencedirect topics. Here we summarize these results and discuss the implications in vitro folding studies have for understanding the pathobiology of cf. Aug 21, 2015 cystic fibrosis cf is a disease caused by aberrant expression, or misfolding, of cftr. The cystic fibrosis transmembrane conductance regulator cftr protein is a cyclic amp campregulated chloride channel expressed in the plasma membrane pm of secretory epithelia in the airways, intestine, pancreas, testis and exocrine glands, as well in some nonepithelial cell types.
Until recently, the standard of care in cystic fibrosis treatment focused on preventing and treating complications of the disease. Investigation of diseasecausing variants such as f508del is resolving the mechanisms underlying cystic fibrosis transmembrane conductance regulator cftr folding and will inform rational design. Cystic fibrosis cf is an inherited disorder caused by mutations affecting the. The cystic fibrosis transmembrane conductance regulator cftr protein helps to maintain the balance of salt and water on many surfaces in the body, such as the surface of the lung. Cystic fibrosis cf is a heterogeneous multiorgan disease caused by mutations in the cftr gene leading to misfolding and other defects and consequent dysfunction of cftr protein. Pedersen department of biological chendshy, the johns hopkins university, school of. Cftr functions as a cyclic adenosine monophosphatedependent anion channel that transports chloride and bicarbonate across. Scltool of medicthe, 725 north wolfe street, baltimore, md 21205, usa received 24 july 1992. Therapeutic approaches to proteinmisfolding diseases nature.
Cystic fibrosis is an autosomal recessive disorder due to mutations in cftr gene leading to abnormality of chloride. Like many variant proteins triggering misfolding diseases, mutant cftr has a. Cystic fibrosis is a common fatal genetic disease caused by mutations in. Modulation of the maladaptive stress response to manage diseases of protein folding daniela martino roth1, darren m. Despite this diversity, most individuals with cf carry at least one cftr allele whose product is synthesized but fails to mature or to proceed beyond the endoplasmic reticulum er within the cell. Both absorptive and secretory processes are affected by an underlying membrane defect in cl permeability. Volume 312, number 1, 79 febs 11677 november 1992 1992 federation of european biochemical societies 001a579392a5. A significant challenge in the development of such assays is the inherent complexity of studying the folding of fulllength cftr protein. Modulation of the maladaptive stress response to manage. Protein structure could unlock new treatments for cystic. Cystic fibrosis cf is a fatal protein misfolding disease that affects more than 80,000 people worldwide and is characterized by progressive lung disease and pancreatic dysfunction 3. Phenylalanine508 mediates a cytoplasmicmembrane domain. When the protein is not working correctly, chloride a component of salt becomes trapped in cells.
The survival rate of patients with cystic fibrosis cf continues to improve. Cystic fibrosis cf, the most common lethal genetic disease in the caucasian population, is caused by lossoffunction mutations of the cf transmembrane conductance regulator cftr, a cyclic ampregulated plasma membrane chloride channel. Cystic fibrosis is a common fatal genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr 1 gene1, 2, 3. Now in its second phase of development, the content is reflected in several forms of causeeffect relationships including.
Mutations of the cftr gene affecting chloride ion channel function lead to. The most prevalent mutation in cf patients is a deletion of phe 508. The deletion of phenylalanine 508 in the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator is directly associated with 90% of cystic fibrosis cases. Cystic fibrosis cf, a fatal genetic disorder predominant in the caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene. Understanding more about the mutations in the chloride channel protein cftr that cause the disease may lead to improved and targeted therapies.
Cystic fibrosis cf is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene and remains one of the most common lifeshortening genetic diseases affecting the lung and other organs. Cystic fibrosis a multiorgan protein misfolding disease ncbi. Cystic fibrosis cf, the most common lethal autosomal recessive genetic disorder among the white population, is caused by mutations in the cf transmembrane conductance regulator cftr gene, with the most common mutation. Cf affects the epithelial lining of many organs but most significantly the airway epithelium of the lung. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of cf lung disease. It affects the respiratory, gastrointestinal, glandular and reproductive systems. Towards next generation therapies for cystic fibrosis. Cystic fibrosis cf is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene and remains one of the most common fatal hereditary disorders worldwide. If both of your parents are carriers of the cf gene mutation, you have a 25 percent chance of being born with this. F508 mutation in the first nucleotide binding domain nbdi alters the ability of the domain to fold into a functional threedimensional structure.
Extensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics. This protein is a promising target for the development of effective drugs to treat cystic fibrosis. Correcting the folding defect may have therapeutic benefit for the treatment of cystic fibrosis. Most mutant nascent chains do not pass quality control in the er, and those that do remain thermally. Adrp is a human protein folding disease that is frequently caused by a prolinetohistidine mutation at position 23 of. Notably, when conditions are altered to promote folding of the mutant protein, it can assume a functional conformation. Cystic fibrosis cf is a fatal genetic disease caused by abnormalities in fluid and electrolyte transport in exocrine epithelia. Codon bias and the folding dynamics of the cystic fibrosis. A posttranslational modification code for cftr maturation. Cystic fibrosis cf is a fatal protein misfolding disease that affects more than 80,000 people worldwide and is characterized by progressive lung disease and pancreatic dysfunction. The discovery of the cystic fibrosis transmembrane conductance regulator cftr gene 25 years ago set the stage for. The typical affects of cf is a production of thick, sticky mucus that clogs the lungs and leads to lifethreatening lung infection, and obstructs the pancreas preventing proper food processing. Treatments only manage the symptoms and eventually are insufficient.
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