Cystic Fibrosis Or Cf Biology Essay

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The disease is caused by mutations in a gene located on the long arm of chromosome 7, which encodes a transmembrane protein, CFTR Cystic Fibrosis transmembrane Conductance Regulator, which belongs to the family of ATP-azica protein activity and acts as a chloride channel in the apical pole of epithelial cell membrane. In addition, the protein is involved in regulation of sodium channels, HCO3-transport occurs through epithelial cell membranes and can act as a conduit for other proteins, such as glutathione. Recent proteomic studies have shown that CFTR interacts with many intracellular proteins, but physiopathological relevance of these interactions has not yet been fully elucidated (after Felix Ratjen, 2009).

After genetic defect detection in 1989 from the gene involved in cystic fibrosis, it was thought that a limited number of mutations causing the disease, but so far have been described more than 1,500 different mutations. Almost all are point mutations or small deletions (from 1 to 84 bp). However, it is important to understand that most are rare and functional consequences of many of them are hard to understand. In fact less than 10 mutations occur with a frequency greater than 1%, while the most common mutation worldwide, characterized by the deletion of phenylalanine at position 508 (ΔF508 - Phe508del) (deletion of three base pairs from the exon 10), is about 30-80% of patients with cystic fibrosis, according to the ethnic group affected (by Felix Ratjen, 2009).

CFTR gene mutations can be grouped into six different classes, divided in relation to their functional consequences at the cellular level (Figure 1):

-Class I: protein is not synthesized;

-Class II: CFTR is poorly processed in the Golgi apparatus;

-Class III protein is not functional;

-Class IV: the conductance abnormal CFTR;

-Class V: CFTR has a partially defective synthesis;

-Class VI: CFTR is degraded faster.

Mutations in Class I, II, III are more common and is associated with pancreatic insufficiency, whereas mutations in classes IV, V and VI are rare and patients exhibit pancreatic (after Felix Ratjen, 2009).

Figure 1. adapted from Roberta Rodrigues, Carmen S. Gabetti, Karla P. Pedro, Fabio Valdetaro, Maria IM Fernandes, Patrícia Magalhães KR, José N. Januário, Léa MZ Maciel, Cystic fibrosis and neonatal screening, Cad. Saúde Pública suppl.4 vol.24, 2008.

CFTR gene contains about 250-280 kilobaze, consisting of 27 exons. This encodes a glycoprotein composed of 1480 amino acids, which form five domains: two transmembrane domains, each with 6 openings in α-helix, two nucleotide domains (NBD) in the cytoplasm, interconnected transmembrane regions and a field regulator (R), linking each transmembrane domain. Ion channel opens only when regulatory region was phosphorylated by protein kinase A (PKA) and the bound ATP nuceotidic.

Figure 2. Adapted from

The consequence is the absence of genetic abnormalities or inadequate functioning chloride channels at the cellular level, which translates into impaired chloride transport in mucous and serous glands of most organs. These secretions will have a low water content will be viscous, adherent to epithelium excretory ducts and difficult to eliminate outward. Their accumulation occurs while impaired and destruction of various organs (lung, pancreas, liver, intestine, reproductive organs). Skin sweat occurs with high concentrations of salt.

Mucoviscidosis vary in severity depending on CFTR mutations and environmental factors and is presented in several forms, some of which cause early death of children, as a result of progressive obstructive lung disease bronchiectasis, other characterized by pancreatic insufficiency and progressive obstructive pulmonary disease during adolescence with increased frequency of hospitalization in adulthood, while others manifested by recurrent bronchitis or sinusitis and infertility in young men. Clinical presentation, age at diagnosis, severity of symptoms and the rate of disease progression varies widely involved organs (after Samuel M Moskowitz, 2008).

Classic cystic fibrosis diagnosis is established on the basis of clinical and anamnestic characteristics and is then confirmed by sweat test or molecular analysis.

70% of patients the diagnosis is established before the age of 1 year, usually in the first months of life. However, there are patients for whom the diagnosis is confirmed only after the age of 10 years.

The diagnosis of CF can be determined if the suspected persons:

1. one or more phenotypic features of CF;

2. CFTR function abnormalities shown:

Presence of disease-causing mutations in the CFTR gene;

- Abnormal chloride in quantitative pilocarpine iontophoresis sweat (> 60 mEq / L);

Or specific values ​​of nasal potential difference.

Sweat test remains the gold standard in diagnosing the disease and assess the concentration of chloride ions and sodium in sweat. Normal levels of electrolytes in sweat fall <40mMol / L are positive values ​​in children> 60 mmol / L, and in adolescents and young adults> 70 mmol / mm; equivocal values: between 40-60 mmol / L repeat binding and it interprets the clinical context. A chloride concentration greater than 60 mmol / L in sweat, at two different sets diagnosis of disease.

False positive results may be associated with Hurler syndrome and the false negatives can occur with acute loss of salt. Where CF is suspected in an individual with hyponatremia and hypochloremia, sweat test should be postponed until the restoration of electrolyte balance.

In the following special cases genetic testing is the initial diagnostic test:

-Utero diagnosis in high-risk fetuses (in 2002, 4% of newly diagnosed individuals were identified through prenatal diagnosis);

-Prenatal testing of fetuses with low risk but ultrasound images suggestive of disease;

-Newborn screening (in 2002, 12.8% of newly diagnosed individuals were identified through neonatal screening);

-Testing symptomatic infants (meconium ileus with) that are too small to produce an adequate amount of sweat;

-Symptomatic testing a person's relatives identificate6 CFTR mutations.

Because cystic fibrosis is transmitted autosomal recessive brother at conception each affected individual has a 25% chance of being a carrier and present condition, 50% chance of being an asymptomatic carrier and 25% chance of being nepurtător and not be affected.

They are paying on prenatal testing of fetal cells obtained by chorionic villus sampling taken at about 10-12 weeks of gestation or by amniocentesis usually about 15-18 weeks of intrauterine life.

Postnatal sweat test should be performed in all patients was suspected cystic fibrosis.

Genetic testing plays an important role in the detection of mutations with important implications in the determinism of certain phenotypes. The best correlation between genotype and phenotype is related to pancreatic function. The most common mutations were classified into two categories: those that cause pancreatic insufficiency and those associated with normal pancreatic function (called "pancreatic sufficient" PS). People without pancreatic damage usually have one or two mutant alleles of type PS, which are dominant in the pancreatic phenotype.

In contrast, genotype-phenotype correlation is generally weak in cystic fibrosis lung disease. Lung disease among people with identical genotypes vary widely, a plausible explanation is interference of environmental factors.

ΔF508/A455E mutations were heterozygous with better lung function compared to individuals homozygous for ΔF508.

Severity of lung disease in people with one or two mutations R117H poly T region depends on the length of the intron 8, so if the patient presents 5T variant in the cis configuration usually develops lung disease and those with variant 7T and 9T have a phenotype very variable that can expand the absence of pulmonary manifestations to moderate forms of the disease.

Since A455E and R117H mutations are associated with normal pancreatic function, less severe lung disease observed in these individuals could be due to better nutritional status.

A negative genetic test targeted mutations can not exclude the disease. Because mutations are described over 1000, the market there are several diagnostic kits that can detect the most common mutations for a given geographic area or population. To truly suspicious cases can resort to complex methods of genetic analysis of DNA (sequencing).

American College of Medical Genetics recommends screening using a panel carriers which highlights 23 mutations, which includes most mutations that have a higher frequency of 0.1% in the general U.S. population. Mutation screening list but can be supplemented with other mutations to improve detection sensitivity for certain ethnic groups.

Genetic tests are available for screening asymptomatic individuals who want to know whether they are carriers of the defective cystic fibrosis gene and involves usually pre-test interviews, and advice on the possible impact of positive and negative test results. This type of genetic analysis allows parents to find out if they have an increased risk of having a child with cystic fibrosis.

Carrier screening for cystic fibrosis recommended the following persons:

- Adults who have relatives with cystic fibrosis;

- Partners of people with cystic fibrosis, if a partner has cystic fibrosis and the other is a carrier of the defective cystic fibrosis gene, the child will have a 50% chance of developing the disease;

- Couples wishing to conceive children.

If investigations reveal that a person is a carrier of the defective cystic fibrosis gene is necessary and partner testing. For a child to develop the disease, both parents must be carriers of the mutated gene. If the tests are negative partner are minimum chances for the child to develop the disease.

1. Felix Ratjen, MD PhD FRCP (C). Cystic Fibrosis: pathogenesis and Future Treatment Strategies. In respirators 2009 May, 54 (5) :595-605.

2. Girish D Sharma. Cystic Fibrosis,, Ref Type: Internet Communication.

3 John Popa Liviu Pop, Zagorca Popa, Casandra CILT. Guide management in CF-(CF).

4. Samuel M Moskowitz, James F Chmiel, Darci L Sternen, Edith Cheng, and Garry R Cutting.CFTR-Related Disorders. Gene Reviews, 2008. Reference Type: Internet Communication.

Student: Irina Philip

Genotypes and phenotypes of the disease milder

Pulmonary disease

Lung disease results from clogging the airways due to mucus accumulation, decreased mucociliary cleaning the resulting inflammation. Inflammation and infection cause injury and structural changes in the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, excess phlegm secretions and decreased physical capacity are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow endlessly and cause pneumonia. In later stages changes occur in the structure pulmonary pathology such as major airways (bronchiectasis), further exacerbate the difficulty in breathing. Other symptoms include coughing up blood (hemoptysis), high blood pressure in the lungs (pulmonary hypertension), heart failure, difficulty in body oxygenation (hypoxia), and respiratory failure that require assistance with breathing masks such as cars bilevale the pressure to respiratory or fans.

Staphylococcus aureus, Haemophilus influenza and Pseudomonas aeruginosa are the three most common organisms causing lung infections in patients with cystic fibrosis.

In addition to typical bacterial infections, people with CF often develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the fungus Aspergillus fumigatus causes worsening of breathing problems.

It was suggested that those individual cases ABPA may also be related to abnormalities in the CFTR gene. A systematic screening study of ABPA patients, all who had normal concentrations of chloride in sweat, revealed a significantly higher frequency of CFTR gene mutations compared with patients with chronic bronchitis and general population. These abnormalities in the CFTR gene can contribute in some way to the development of ABPA.

Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause lung damage and does not respond to common antibiotics.

Mucus in the paranasal sinuses is equally thick and may also cause, blockage of the sinus passages, leading to infection. This can cause facial pain, fever, nasal drainage, and headaches. People with CF can develop a massive accumulation of nasal tissue (nasal polyps) due to chronic inflammation arising from sinus infections. Recurrent sinus polyps may occur in 10% to 25% of patients with CF. These polyps can block the nasal passages thereby increasing breathing difficulties.

Latest disease associated with CFTR - although incomplete set - is asthma, which is a very common lung condition. Following a Danish population study tested the association between heterozygosity for ΔF508 mutation and obstructive pulmonary disease. It was an overrepresentation of this allele among people with asthma, especially those with both asthma and airway obstruction as well. However, previous studies done on smaller populations with asthma have found a negative association or no association for this allele. Two subsequent studies that used a complete mutation scanning technique in patients with asthma in ethnically diverse populations have found an increase CFTR mutations or variants in certain populations. There was no association between asthma severity and the presence or absence of CFTR mutations.

Gastrointestinal tract

Before prenatal screening and newborn cystic fibrosis was often diagnosed when a newborn infant failed to pass through feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 5-10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common and occurs in about 10% of cases of children with CF and is caused by increased fecal volume, malnutrition, and increased intra-abdominal pressure due to coughing.

Thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for secreÅŸia of digestive juices that help digest food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). Pancreatic ducts are completely blocked in more advanced cases, usually seen in older children or adolescents. This causes atrophy of exocrine glands and progressive fibrosis.

The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption and malnutrition increase the growth and development slowed the loss of calories. Resulting hypoproteinemia may be severe enough to cause generalized edema. People with CF also have difficulties in absorbing fat-soluble vitamins A, D, E and K.

In addition to the pancreas problems, people with CF have heartburn, intestinal blockage by intussusception, and constipation. Older people with CF may develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.

Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF. It is mainly associated with severe CFTR mutations, where both alleles are completely non-functional (eg ΔF508/ΔF508). Occurs in 10% -15% of patients with "severe" and "mild" CFTR mutation where there still is how little CFTR activity, or where there are two "mild" CFTR mutations. In these cases mild pancreatic exocrine function is compromised, so there is a need for additional enzymes. Usually no other GI complications in phenotypes with pancreatic sufficiency and, in general, such people usually excellent growth and development. Despite this, idiopathic chronic pancreatitis may occur in a subset of people with CF who have pancreatic sufficiency and is associated with recurrent abdominal pain and complications can cause patient death.

Thick secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to scarring and nodular (cirrhosis). Liver fails to cleanse the blood of toxins and produces important proteins, such as those responsible for blood clotting. Liver disease is the third of the most common causes of death associated with CF.

Male reproductive system

Congenital bilateral absence of the vas deferens (CBAVD) is the most investigated form of obstructive azospermiei with a frequency of about 1-2% among men with infertility. Full mutation screening of patients with CBVAD revealed a spectrum of different but overlapping set of genotypes CFRT reverse mutation compared to those seen in people with CF. Genotype in these patients consists of at least one mild mutation not typical for those with CF.

The most important characteristic genotyping for these patients is a high prevalence of RNA splice variant, IVS8-5T. It is one of the three known alleles with a variable number of thymidine in politimidin tract (T-tract) of the splice acceptor site on the intron 8. Analysis of individual transcripts carriers of different genotypes of T tract showed that they produce varying amounts of CFTR mRNA lacking exon 9, which produces a defective chloride channel function. Incomplete transcript amount was in inverse proportion to the length of allele T-tract. So the 5 thymidine, 5T, is typically associated with the highest proportion of aberrant CFTR variant with the smallest amount of normal variant. 5T allele alone rarely produce FC but can modify phenotypic effect or other mutations. One of them, R117H, a mutation is present misssense both those with CF and those with CBVAD. Analysis cosegregării T-tract variants with this mutation in groups of patients with CF and CBAVD showed a tendency to associate R117H allele variant 5T in patients with CF and 7 T in patients with CBAVD.

Other studies of potential mechanisms underlying differential phenotypic expression in patients with CF or CBAVD were made by analysis of CFTR transcription in nasal epithelium and vas deferens in normal individuals with different genotypes T-tract. Considerable number of splices aberrant transcripts were observed in cells of vessels compared to nasal cells from the same individual. Therefore, nasal epithelium cells produce more functional CFTR.

A higher than expected proportion of CF mutations or variants were observed in other common forms of infertility, including obstructive azospermia or oligospermia. Unlike observations in patients with CBAVD men with obstructive azospermia rarely housed two different CFTR mutations. It was recently proposed that in the absence of CFTR mutations defined, common polymorphic variants of CFTR can lead to obstructive azospermia. Two variants like these, repeated variable (TG) m tract before politimidină common variant in intron 8 and M470V in exon 10, are involved as modulators of CFTR. Genotype association with M470V variant produces less functional CFTR is a risk factor for the development of obstructive azospermiei. Process of sperm maturation may be delayed in patients with CBAVD.

Sweat ducts

An interesting phenotype, presenting a high concentration of chloride in sweat in the absence of other symptoms of CF, was described in a patient with a nonsense mutation, S1455X. This mutation truncates 26 amino acids at the C-terminus of the protein product. This secondary mutation in this patient was severe and caused FC classical homozygous index cases of kinship and so unusual presentation was attributed nonsense mutation. CFRT S1455X variant showed that the protein was processed normally and it is functional and suggest that the extent of the C-terminal amino acids play the same role in the sweat glands. Selective effect of the nonsense mutation shows tissue specific differences in the consequences of particular mutations and subsequent contributions to CFTR-dependent phenotypic variation in CF.

The Braekeleer M, hoop C: mutations in the cystic fibrosis gene in men with congenital bilateral Absence of the vas deferens. Mol Hum Reprod 1996, 2:669-677.

Patrizio P, Zielenski J: Congenital Absence of the vas deferens: A mild form of cystic fibrosis. Mol Med Today 1996, 2:24-31.

Pier, GB, Grout, M., Zaldi, TS, Olsen JC, Johnson LG, Yankaskas, JR, Goldberg, Role of mutant CFTR JB in hypersusceptibility of cystic fibrosis patient's to long infections. Science 271: 63-67, 1996.

Student: Loredana Radulescu

Cystic fibrosis is an autosomal recessive genetic disease that affects mainly the lungs, pancreas, liver and intestines. It is characterized by abnormal transport of chloride and sodium in the epithelium, leading to the emergence of viscous secretions. (Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. (2004). "Cystic fibrosis adult consensus conference report." Chest 125 (90010): 1-39, PMID: 14734689).

Cystic fibrosis occurs due to a mutation in the gene CFTR (Cystic Fibrosis transmembrane Conductance Regulator Gene). The most common mutation is a deletion of three nucleotides (ΔF508) that leads to loss Phenilalanină amino acid (F) at position 508 of the protein.

Although this mutation is responsible for approximately 70% of cases of cystic fibrosis, there are about 1,500 other mutations that can cause disease (Bobadilla JL, Macek M, Fine JP, Farrell PM (June 2002). "Cystic fibrosis: a worldwide analysis of Incidence CFTR mutations-correlation with time and application to screening. "Hum. Moved. 19 (6): 575-606. PMID: 12007216).

Although most people have two functional alleles of the CFTR gene, only one allele is necessary for healthy preventing disease since it is an autosomal recessive disease.

CFTR gene is located on the q31.2 locus of chromosome 7, has a length of 230,000 base pairs and produces a protein of 1480 amino acids in length. In terms of structural gene is a gene known as ABC (Rowe SM, Miller S, Sorscher EJ (May 2005). "Cystic fibrosis". The New England Journal of Medicine 352 (19): 1992-2001, PMID: 15888700 ). Gene product CFTR is a chloride ion channel important in creating sweat, digestive juices and mucus. Mutations in the gene affect the operation of chloride channels, preventing them to regulate the flow of chloride ions and water across cell membranes. As a result, the cells of the lungs, pancreas and other organs produce a highly viscous mucus that blocks the airways and other means of transport of fluids in the body. (Http://

Clinical signs include cystic fibrosis airway inflammation, chronic bronhopeumopatii, cysts, abscesses, parenchymal fibrosis, digestive problems (meconium ileus in 15-20% of newborns with pancreatic insufficiency malabsorption) and impaired reproductive function (approximately 95% of men are infertile due to absence of corresponding ducts) (

Regarding complications of cystic fibrosis, the most common is chronic respiratory infection, but are met and intestinal problems such as intestinal obstruction, gallstones and rectal prolapse, coughing up blood, chronic respiratory collapse, diabetes, infertility, liver disease, cirrhosis biliary pancreatitis, malnutrition, nasal polyps and sinusitis, ostroporoza and arthritis, recurrent pneumonia, pneumothorax and cardiac problems

Although fibrosis chiostică no cure, the disease can be kept under control for a longer time if the person affected is a treatment to slow the decline of organs.

Treatment for lung problems includes antibiotics to prevent or cure lung and sinus infections, inhale to open the airway, administration of high concentrations of saline solutions, making influenza vaccine, going sometimes to lung transplantation.

Digestive problems can be alleviated by following a diet rich in protein and calories by older children and adults, administration of pancreatic enzymes to help absorb fats and proteins, and taking vitamins - especially vitamins A, D, E and K.

Care and home monitoring include avoiding tobacco and tobacco smoke, dust, dirt, chemicals and mold, cleaning or spit or mucus secretions in the airways once to four times a day, consuming large amounts of liquid and practicing exercise two to three times a week (

Student: Daniela De-Santha