Theme : Genetic deseases

Cystic Fibrosis (CF) The cystic fibrosis transmembrane conductance regulator (CFTR) gene codes for a protein also known as CFTR. The CFTR protein resides in the surface of epithelial cells which line the lungs, digestive system and sweat glands. The symptoms of CF are caused by the inability of the CFTR to release chloride leading to the production of thick, sticky mucus in specific organs. Since its discovery in 1989, more than 1,000 mutations of this single gene that can cause CF have been identified. Often, these mutations either substitute one DNA base – the building material of DNA – for another or delete a small number of DNA bases. The most common mutation, present in about 70 percent of patients with CF, is called F508del. In this mutation, three base pairs of the CFTR gene are deleted leading to the loss of an amino acid called phenylalanine (abbreviated F) at position 508 of the CFTR protein. In normal cells, the CFTR protein acts as a channel that transports chloride into and out of cells, and regulates the passage of salts. The CFTR can also transport other ions and chemicals such as bicarbonate.

Watch the lesson to understand why the organs that are typically involved in CF are the skin, pancreas and lungs. Take notes on your copybook and try to explain with your classmate by drawing a diagram for each case. https://www.youtube.com/watch?v=ucbxYIVztz8

Help document The location of the CFTR protein, which is found in several organs, determines where the symptoms of CF occur.

The Sweat Gland Sweat is produced in glands under the skin, transported to the skin surface through ducts, where some of the salt and water are reabsorbed. In normal skin functioning, as sweat moves along the duct most of the sodium and chloride—the components of salt—are reabsorbed. This is driven by a large force drawing sodium into cells lining the sweat duct. The chloride flows through the CFTR channel, while sodium flows into the cell through epithelial sodium (Na) channels (ENaC) in the apical membrane. The salt reabsorption process is markedly abnormal in people with CF. Chloride transport is virtually eliminated because CFTR, which is the main way for chloride to enter the apical, or top, surface of cells is defective. Chloride must travel through the CFTR, located on the surface of the duct cells, at the same rate as sodium to maintain a balance of electrical charges. This results in very little sodium and chloride reabsorption, leading to a high salt content in CF sweat—so high that the sweat chloride concentration is the most reliable single test for CF.

The Lung The lung’s airways are covered with a thin, moist film called airway surface liquid, or ASL, a salt-containing liquid and a mucus gel layer. The ASL traps bacteria and foreign particles, while cilia on the surface of airway cells constantly move the particles out of the lungs and toward the mouth. This process, called mucociliary clearance, or MCC, is an important defense mechanism that protects the lungs from infection. ASL also contains antiproteases, antioxidants, antibodies and other substances that work together to neutralize or destroy invading organisms without damaging the lungs. In CF airways, decreased chloride transport is coupled with excess sodium transport out of the surface liquid. Since water follows the flow of sodium, the ASL loses volume and the mucus gel layer becomes dehydrated.

The Pancreas The exocrine pancreas produces enzymes that digest food. Cystic fibrosis leads to pancreatitic insufficiency in the majority of individuals with the disease. Pancreatic duct cells also secrete bicarbonate (HCO3) into the intestine to neutralize stomach acid. Bicarbonate is secreted via the CFTR channel. In individuals with CF bicarbonate secretion is defective. Sources: http://www.hopkinscf.org/what-is-cf/basic-science/cftr/function/

To go deeper on CFTR mutations: https://www.youtube.com/watch?v=_j99-xgOIaw http://www.hopkinscf.org/what-is-cf/basic-science/cftr/mutations/ More than 1000 different mutations in the CFTR gene can cause CF. Most of these mutations either substitute one DNA base – the building material of DNA – for another, or delete a small number of DNA bases altogether. The most common mutation present in approximately 70 percent of CF patients is called delta F508 or F508del. This change, or delta, is caused by the deletion of three base pairs of the CFTR gene that lead to the loss of an amino acid called phenylalanine in the CFTR protein. There are several mechanisms by which mutations in the CF gene produce changes in CFTR function. Patients who have some normal CFTR reaching the cell surface tend to have milder symptoms.

Nadine Pellen a dressé la carte de la mucoviscidose Article tiré du journal OUEST FRANCE - Bretagne - Modifié le 03/10/2013 à 02:13

En Bretagne, la mucoviscidose touche une naissance sur 2 928. Une naissance sur 2 400 dans le Finistère, contre 4 400 en France. Sur le littoral du Léon, une personne sur quinze à vingt serait porteur sain du gène! (One in 31 Americans has one copy of a defective CFTR gene...)

Pourquoi cette maladie génétique est-elle plus répandue en Bretagne qu'ailleurs ?

La sociologue léonarde est convaincue que l'histoire remonte au Ve siècle. Aux migrations en Armorique. À partir de l'an 500, des Brittons, chassés par l'avancée des Anglo-saxons s'installent en Armorique. Ces Gallois, Cornouaillais ou Irlandais y ont fait souche, nous léguant une organisation territoriale, une toponymie, une culture, des traditions, une langue. Ils nous auraient aussi apporté la mucoviscidose. C'est l'une des hypothèses, étayée par des éléments troublants, sinon probants, qu'explore Nadine Pellen dans une thèse de doctorat qu'elle a présenté hier, à Roscoff, au Centre de Perharidy, spécialisé dans le traitement de la mucoviscidose. Nadine Pellen est professeur-chercheuse en sociologie à l'Université de Bretagne occidentale. Le gène délétère se serait donc transmis localement de génération en génération sur quinze siècles ? « La consanguinité n'est nullement en cause, précise la chercheuse. En revanche, jusqu'à une époque très récente, le « marché matrimonial » était restreint, on se mariait avec son voisin, ce qui a produit des unions entre apparentés éloignés, entre « cousins à la mode de Bretagne. » Et donc favorisé l'union de deux porteurs sains pouvant donner naissance à un enfant malade. « La mucoviscidose est un drame épouvantable pour de trop nombreuses familles. » Nadine Pellen voudrait que cette étude leur apporte la preuve « qu'elles n'y sont pour rien, que c'est ainsi, que la maladie fait partie de notre histoire collective, de notre héritage culturel et génétique. » Elle voudrait aussi que sa contribution incite un maximum de Bretons et Bretonnes à se faire dépister. « Au moment d'avoir un enfant, chacun prend sa décision en conscience, mais il faut le faire en toute connaissance, plaide-t-elle, nous sommes tous potentiellement concernés. » Source : http://www.ouest-france.fr/bretagne/nadine-pellen-dresse-la-carte-de-la-mucoviscidose-1552074