Cystic Fibrosis is characterized by a build-up of thick, sticky mucus that can bring about the onset of progressive damage to the respiratory system and chronic digestive system debilitations. The abnormal mucus can clog airways, which may lead to respiratory conditions and bacterial infections in the lungs, causing chronic coughing, wheezing, and inflammation.
Accumulation of mucus and infectious agents result in permanent lung tissue damage, formation of fibrous scar tissue, and the development of cysts in the lungs. Due to the build-up of mucus, blockage of the pancreatic ducts reduces the production of insulin and prevents digestive enzymes from reaching the intestines; the build-up of mucus does not only occur in the respiratory tissues, but also in other organs such as the pancreas and the reproductive tract. These issues may lead to diarrhea, malnutrition, poor growth, and weight loss. Cystic Fibrosis Related Diabetes Mellitus (CFRDM) may develop in adolescence or in adulthood. Most men affected have Congenital Absence of the Vas Deferens (CBAVD), which is a condition in which the vas deferens is blocked by the thick mucus associated with Cystic Fibrosis which renders it unable to properly develop; which would render the male infertile. Women may experience complications during pregnancy. Affected babies may develop Maconeum Ileus, a blockage of the intestine which may occur shortly after birth.
Generally, Cystic Fibrosis occurs when there is a mutation on Human Chromosome-7; this chromosome spans approximately 159 million base pairs (bp) and represents 5% of the total DNA in cells. Changes in the structure or number of copies of a gene on chromosome-7 can lead to somatic cancers of immune system cells. A loss of part, or all, of one copy of chromosome-7 is common in Myelodysplatic Syndrome, which increases the risk of development of Leukemia. The gene locus 7q31.2 is found on the long arm of the locus q31.2, whose structure is 250,000 bp long with 27 exons connected. The protein size is 1480 amino acids long and it’s molecular weight is 168,173 Daltons; the protein function includes CFTR regulation of transport pathways and the instructional layout of a channel that would transport negatively charged chloride ions into and out of cells as well as regulate the passage of positively charged sodium ions. The flow of chloride ions helps control the movement of water in tissues which is necessary for the production of thin, freely flowing mucosal membranes. Its coding sequence is 4443 bp long within the mRNA code, which is 6129 bp long Intron-free. Introns are parts of genes that do not directly code for proteins and range in size from 10 bp to 1000’s of base pairs; Introns are found in multicellular eukaryotes and are present in the initial RNA Transcript, which need to be removed for mRNA to direct the production of proteins. Intron-Splicing necessitates vital precision because any left-over intron nucleotides or deletion of exon nucleotides may result in faulty production of proteins during transcription and later translation. Exons are expressly sequenced parts of DNA that are converted into mature mRNA. Splicing of RNA tends to occur at the dinucleotide GU at the 5’ end and AG at the 3’ end; this is carried out by small nuclear ribonucleoproteins (snRNPs) which bind to the 5’ and 3’ ends of an intron and remove the sequence, leaving the exons to link.
CFTR, or Cystic Fibrosis Transmembrane Conductance Regulator (ATP-binding cassette sub-family C, member 7) is the protein which functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. CFTR belongs to a family of genes called ATP-binding cassette transporters, or ABC; CFTR also belongs to the family of genes called ATP, or the ATPase Superfamily. Disorders associated with the CFTR include Cystic Fibrosis and Congenital Bilateral Aplasia of the Vas Deferens (CBAVD).
“Whole-genome methods provide an attractive approach to identify modifier loci of Mendelian disorders. However CF presents numerous challenges, such as: collecting multiple years of lung function measures to accurately classify lung disease severity; selecting the appropriate study design to identify common and rare variants; accruing sufficient sample sizes, and accounting for potential interaction between CFTR and modifier loci. To overcome these challenges, we formed a North American CF Gene Modifier Consortium to identify modifiers of lung disease severity and other phenotypes. For lung disease in CF, the forced expiratory volume in 1 second (FEV1) is the most clinically useful measure of lung disease severity and is a well-established predictor of survival….” (1)
Persistence of inflammation and infection caused by opportunistic pathogens leads to airway damage and abnormal dilation of the bronchi, or bronchiectasis, and respiratory failure. Air may become trapped in the small airways, resulting in hyperinflation and atelectasis. Aside from these conditions, secondary respiratory infections are likely to occur. Metabolic functions are increased due to physiological reactions related to frequent infections, therefore patients with CF are reported to have a voracious appetite; the alteration of metabolic functions are the result of excessive electrolyte loss or imbalance brought on by the mutation of the deltaF508-CFTR gene and its lack on chloride trans-membrane transport provision ultimately seen through perspiration, salivation, and mucous secretion.
Two genetic loci that are involved in the associated severity of Cystic Fibrosis include 20q13.2 and 11p13. The 20q13.2 locus is found on the long arm of Human Chromosome-20 and is involved in the onset of cancers such as colorectal and breast cancer, while the 11p13 locus is found on the short arm of Human Chromosome-11 and is involved in the opening of chromatin and DNAase hypersensitivity patterns in reference to cell-type specificity. These two loci are involved in the mutation of CFTR known as deltaF508, which is a specific deletion of three nucleotides that make up a codon for phenylalanine at position 508, therefore a person with the deltaF508-CFTR mutation will produce the protein which lacks phenylalanine; this prevents an escape from the endoplasmic reticulum in affected cells and inhibits the transport of chloride ions. Cystic Fibrosis is a homozygous recessive gene, therefore two deltaF508-CFTR mutation copies are necessary for expression of the disease.
As previously stated, Cystic Fibrosis not only affects pulmonary organs but also the digestive and reproductive systems; physiologic alterations and inhibition of maturation are also the result of this inherited autosomal recessive disorder. The CFTR gene regulates the ion flux at epithelial surfaces, and a mutation in position 508 of the CFTR glycoprotein responsible for the transport of negatively-charged chloride ions across mitochondrial membranes is the most common mutation in the onset of Cystic Fibrosis with relation to its severity. Over 1,500 different CFTR mutations have been recorded on chromosome 7. The defective genes and their products are expressed in the sweat ducts, airways, pancreatic ducts, intestines, and the vas deferens in males or the reproductive organs in females. Essentially, it is the deletion of the amino acid, Phenylalanine, which brings upon the onset of the CFTR mutation. This complete removal offsets the CFTR sequence and inhibits the transport of chloride ions into and out of the affected epithelial cells.