Cystic fibrosis (CF) is a disease which is usually inherited through families. In this disease, patients’ body especially lungs and digestive tract produce thick, sticky fluid, called mucus. Importantly, it is one of the most common chronic lung diseases in children and young adults which could be a life-threatening if not taken care of properly by an experienced physician, because collection of sticky mucus in airways, may lead to lung infections and serious digestion problems. The disease sometimes also affects the sweat glands and a man's reproductive system.
Anyways, the reason that prompted me to write this article is due to my indirect role in the understanding of the Cystic Fibrosis at mechanistic level.
In order to develop CF, a person must inherit two defective CF genes - one from each parent, this is the reason that a majority of people carry the defective CF gene, but do not have any symptoms. An estimated 1 in 29 Caucasian Americans have the CF gene. While CF has primarily been considered as one of the most deadly inherited disorder among Caucasians (white people from West) recent reports suggest its presence in Indian subcontinent too, however, its precise magnitude is not known. Studies on migrant Indian population in United States and United Kingdom estimate that one out of each 10,000 Indians could be affected with CF. CF in Indian children is usually diagnosed late and in advanced stage. Children are more malnourished and may have clinically evident deficiency of fat soluble vitamins such as A, D, E and K. Diagnostic facilities in form of sweat chloride estimation and genetic studies are not available readily. While in recent years Indian diagnostic laboratories have introduced several state-of-art molecular tests for various viral and genetic diseases, lack of ample amount of scientific data on complete genetic make-up of CF in India (as Indian patients harbor different mutations in their CF genes than their western counterparts) makes it even more difficult to diagnose this disease at molecular level.
Symptoms
Symptoms in newborns may include:
Failure to gain weight normally during childhood which ultimately results in slow growth
No bowel movements in first 24 to 48 hours of life
Salty-tasting skin
Symptoms related to bowel function may include:
Belly pain from severe constipation
Increased gas, bloating, or a belly that appears swollen (distended)
Nausea and loss of appetite
Clay or pale colored stools with foul smelling, have mucus, or that float
Symptoms related to the lungs and sinuses may include:
Coughing or increased mucus in the sinuses or lungs
Fatigue
Nasal congestion caused by nasal polyps
Recurrent episodes of pneumonia.
Symptoms in someone with cystic fibrosis include:
Fever
Increased coughing
Increased shortness of breath
Loss of appetite
More sputum
Sinus pain or pressure caused by infection or polyps
Symptoms that may be noticed later in life:
Infertility (in men)
Repeated inflammation of the pancreas (pancreatitis)
Respiratory symptoms
Signs and tests
A blood test is available to help detect CF. The test looks for variations in a gene known to cause the disease. Other tests use to diagnose CF include:
Immunoreactive trypsinogen (IRT) test is a standard newborn screening test for CF. A high level of IRT suggests possible CF and requires further testing.
Sweat Chloride Test is the standard diagnostic test for CF. A high salt level in the patient's sweat is a sign of the disease.
Other tests that identify problems that can be related to cystic fibrosis include:
Measurement of pancreatic function
Management of the disease
To educate masses especially those from India, I presented a very simple outline of Cystic Fibrosis here, however, please keep in mind that this is one of those diseases with so complicated mechanism that there is no straightforward way to diagnose the disease. However, be assured that an early diagnosis of CF and a comprehensive treatment plan can improve both survival and quality of life. I will not discuss the treatment modalities here, so if you have any further questions/doubts, please discuss it with your physician/pediatrician. However, I would like to mention that most children with cystic fibrosis are fairly healthy until they reach adulthood. They are able to participate in most activities and should be able to attend school. Many young adults with cystic fibrosis finish college or find employment.
Lung disease eventually worsens to the point where the person is disabled. Today, the average life span for people with CF who live to adulthood is approximately 37 years in western countries, a dramatic increase over the last three decades. Death is usually caused by lung complications.
My connection with Cystic Fibrosis
Anyways, the reason that prompted me to write this article is due to my indirect role in the understanding of the Cystic Fibrosis at mechanistic level.
Well, it is known that Cystic fibrosis is an autosomal recessive inherited disorder caused by alterations in a gene called CFTR, the cystic fibrosis transmembrane conductance regulator gene. CFTR gene encodes a transmembrane protein present at the surface of most epithelial cells. It is proposed that abnormal electrolyte transport caused by defective CFTR gene causes altered mucus viscosity and decreased mucosal defense against infection, which leads to airway plugging, chronic inflammation and progressive destruction of the lung. There are several types of mutations or variations in CFTR gene/protein that result in this disease. However, it is important to notice that the disease progression and its severity do not appear to correlate with the type of CFTR variant and seems to be largely dependent on secondary factors which means there could be more genes/proteins besides CFTR that could indirectly be contributing towards disease progression and could well affect disease prognosis and its clinical management.
In a recent paper published in a reputed journal, Nature Genetics, Dr. Garry Cutting, M.D., from a very prestigious medical school at John Hopkins University and his collaborators identified two new genetic loci on chromosome 11p13 and chromosome 20q13 contributing to variation in lung function in patients with cystic fibrosis. This group conducted a combined genome wide association and linkage study in 3,467 individuals with cystic fibrosis originating from three different study populations. Linkage analysis of 486 sibling pairs from the family based study they identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03).odds = 5.03).
While 3 out of all five genes within the chromosome 20 linkage region are not well characterized in the terms of their structure and function, two of them CASS4-HEPL and Aurora kinase A (encoded by AURKA) are the ones that I have been personally been interested in and involved in the past in a different context.
Well, it was me who first identified and cloned this locus - Chr. 20 orf32, while working at Fox Chase Cancer Center, Philadelphia, in 2008 and designated it as HEPL (for HEF1-Efs-p130Cas-like) protein due to its structural similarity to Cas family proteins which are HEF1, Efs, and p130Cas. Later HUGO gene nomenclature committee gave it an official name CASS4 (Cas scaffolding protein family member 4) because it is now considered as 4th member of Cas family of adapter proteins which are well studied and implicated in many cellular functions including cell attachment, cell migration establishing polarity, invasion and phagocytosis of bacterial pathogens.
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| Expression of HEPL in various tissues and cell types |
I had observed that the human HEPL mRNA and protein are selectively expressed in specific primary tissues and cancer cell lines, and HEPL protein maintains Cas family function in localization to focal adhesions of the mammalian cells, as well as regulation of FAK activity, focal adhesion integrity, and cell spreading.
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| Lung sections stained with Anti-HEPL antibody, which shows high expression levels of HEPL in lung tissues. |
When I saw Dr. Garry Cutting’s paper in Nature Genetics paper, it kind of reaffirmed my earlier hypothesis that HEPL could be involved in lung diseases, as in my own work with this protein while characterizing the molecular pathways pertaining to this protein, I had noticed an unusually high expression of HEPL protein in lung tissues (both normal and cancerous). However, due to my primary interest in Cancer Biology, I kept on working on other aspects of the same protein family. I hope Dr. Cutting who is an expert in the area of Cystic Fibrosis, and other investigators will continue working on the mechanistic connection between HEPL loci on Chromosome 20 and Cystic Fibrosis. Well, the good news is - HEPL being a scaffolding protein may well serve as molecular target because of its interactions with several important kinases such as FAK and Src etc. that I discussed in my 2008 publication. I am very enthusiastic about these findings as they provide deep insight into the causes of variation in lung disease severity in cystic fibrosis and have a great potential for development of new therapeutic targets for this deadly disorder.
