About CF

Cystic Fibrosis

Cystic Fibrosis or Mucovisidosis is Autosomal recessive genetic disorder.

It is an inherited disease characterized by the buildup of thick, sticky mucus that can damage many of the body’s organs. The disorder’s most common signs and symptoms include progressive damage to the respiratory system and chronic digestive system problems. The features of the disorder and their severity varies among affected individuals.

Mucus is a slippery substance that lubricates and protects the linings of the airways, digestive system, reproductive system, and other organs and tissues. In people with cystic fibrosis, the body produces mucus that is abnormally thick and sticky. This abnormal mucus can clog the airways, leading to severe problems with breathing and bacterial infections in the lungs. These infections cause chronic coughing, wheezing, and inflammation. Over time, mucus buildup and infections result in permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs.

Most people with cystic fibrosis also have digestive problems. Some affected babies have meconium ileus, a blockage of the intestine that occurs shortly after birth. Other digestive problems result from a buildup of thick, sticky mucus in the pancreas. The pancreas is an organ that produces insulin (a hormone that helps control blood sugar levels). It also makes enzymes that help digest food. In people with cystic fibrosis, mucus blocks the ducts of the pancreas, reducing the production of insulin and preventing digestive enzymes from reaching the intestines to aid digestion. Problems with digestion can lead to diarrhea, malnutrition, poor growth, and weight loss. In adolescence or adulthood, a shortage of insulin can cause a form of diabetes known as cystic fibrosis-related diabetes mellitus (CFRDM).

Cystic fibrosis used to be considered a fatal disease of childhood. With improved treatments and better ways to manage the disease, many people with cystic fibrosis now live well into adulthood. Adults with cystic fibrosis experience health problems affecting the respiratory, digestive, and reproductive systems. Most men with cystic fibrosis have congenital bilateral absence of the vas deferens (CBAVD), a condition in which the tubes that carry sperm (the vas deferens) are blocked by mucus and do not develop properly. Men with CBAVD are unable to father children (infertile) unless they undergo fertility treatment. Women with cystic fibrosis may experience complications in pregnancy.The CFTR gene controls hydration of the epithelium(the mucous viscosity) through out the body is faulty. So the Mucus gets thicker. For various reasons the chloride channel in the epithelial cells is either absent or functions partially. The epithelial cells are predominantly spread in Pancreas, Gastrointestinal tract, Sweat glands and Lungs.

What is autosomal recessive inheritance?Autosomal recessive inheritance means that the gene is located on one of the autosomes (chromosome pairs 1 through 22). This means that males and females are equally affected. “Recessive” means that two copies of the gene are necessary to have the trait, one inherited from the mother, and one from the father. A person who has only one recessive gene is said to be a “carrier” for the trait or disease, but they do not have any health problems from “carrying” one copy of the gene. Most people do not know they carry a recessive gene for a disease until they have a child with the disease. Once parents have had a child with a recessive trait or disease, there is a one out of four, or 25 percent chance, with each subsequent pregnancy, for another child to be born with the same trait or disorder. This means that there is a three out of four, or 75 percent chance, for another child to not have the trait or disease:

Autosomal recessive

The birth of a child with a recessive condition is often a total surprise to a family, since in most cases, there is no previous family history of a recessive condition. Many autosomal recessive conditions occur this way. As mentioned above, a person who “carries” one copy of an autosomal recessive gene is usually not aware they carry the gene, because they do not show any signs of the disease or condition. It is estimated that all people carry about 20 recessive genes that cause genetic diseases or conditions. Usually a person does not know they carry a recessive gene unless they have the disease in their family, or if they have had an affected child.

Classifications in CF(CFTR Mutatations)

More than 1600 CFTR mutations have been identified; the most common is F508del, which accounts for approximately 66% of all CFTR mutations.[6,7] These mutations are divided into 5 classes based on their effects on CFTR production and the amount of residual CFTR function.[1,4] Although not all mutations fit exclusively into 1 class, the system is helpful when determining which medication may be beneficial for a particular mutation.

Normal CFTR protein production occurs in the nucleus of the cell when CFTR is transcribed into RNA; splicing then occurs to form messenger RNA (mRNA). mRNA travels out of the nucleus to the endoplasmic reticulum (ER) where mRNA is translated into a protein and the protein is folded. From the ER the protein moves to the golgi apparatus and is transported to the cell membrane.[7,8]This results in a normal amount of CFTR protein at the cell membrane and normal chloride transport (Figure 1a). The various CFTR mutations cause disruption at different points in the CFTR protein production process.

Mutations in the CFTR gene can be classified into six classes according to the mechanism by which they disrupt the synthesis, traffic and function of CFTR.

Class 1: Lack of CFTR Synthesis

Class I mutations represent approximately 10% of the CFTR mutations that cause CF in patients worldwide.[1] The mutation causes a premature stop codon, which causes translation of mRNA to stop prematurely. The result is truncated CFTR protein that does not reach the cell membrane .
Class 2: Defective protein Processing
Class II mutations include the most prevalent CF mutation, F508del, which occurs in 88.5% of CF patients in the Cystic Fibrosis Foundation Patient Registry.[1,9] Class II mutations primarily result in trafficking defects.[4] The CFTR protein is not folded properly nor transported to the cell surface. The CFTR proteins stay in the ER and are degraded. Little residual CFTR is maintained. Drugs and supplements which can correct the protein unfolding problem are called correctors.
Class 3:Defective Channel regulation or channel gating
Class III mutations occur in only a small percentage of patients with CF (2–3%).[1]These mutations are called gating mutations. The CFTR protein reaches the cell membrane but the channel does not open properly and chloride transport cannot occur. The supplements which can open the channel for chloride transport are called Potentiators.
Class 4:Defective Chloride conductance
Class IV mutations also are uncommon, causing disease in less than 2% of patients with CF.[1] With class IV mutations, the CFTR protein reaches the cell membrane and some of the protein is functional. However, due to channel narrowing there is reduced chloride transport.
Class 5:Reducd aount of CFTR protein
Class V mutations are the least common. These mutations are caused by splicing defects that result in improper processing of mRNA. Therefore, a reduced number of CFTR proteins reach the surface, but the proteins are able to transport chloride effectively.
Class 6:Increased turnover of CFTR Channel at the cell membrane
The accelerated turnover of CFTR protein at the cell surface reduces the stability of the protein.