Researchers Uncover a Cystic Fibrosis Type That Doesn’t Affect The Lungs
A team of researchers from the University of Pittsburgh has discovered that people with unexplained pancreatic problems might have a previously unknown type of cystic fibrosis that doesn’t affect the lungs.
According to the Cystic Fibrosis Foundation, there are over 30,000 children and adults in the United States suffering from cystic fibrosis (CF), a hereditary disorder in which the patient develops thick mucus, especially in the lungs, scarring in the pancreas, as well as anomalies in the sweat glands, nasal sinuses, intestines, liver, and male reproductive system.
Mutations in the CFTR channel, an ion channel regulating movement of chloride and bicarbonate across cell membranes, can cause complete loss of function and result in cystic fibrosis. One such mutation, CFTRBD, causes a selective bicarbonate defect in channel function, affecting organs that use CFTR for bicarbonate secretion, such as the pancreas, nasal sinus, or vas deferens.
In order to understand the structural and functional requirements of the CFTR channel, the researchers screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously defined CFTR variants, conducting studies on clones of variants found in pancreatitis but not CF. Additionally, they constructed a complete structural model of CFTR for molecular dynamics simulation of wild-type versus mutant forms of this gene, and tested these newly defined CFTRBD variants in non-pancreas organs that rely on CFTR for bicarbonate secretion.
The data, published online in the journal PLOS Genetics, revealed that of the 43 CFTR variants identified, nine not associated with typical CF but reported in patients with pancreatitis were found more commonly in cases (14.2%) than in controls (9.8%).
The investigators then cloned the nine CFTR variants and confirmed that, except for one particular variant, they had normal folding, glycosylation and chloride channel activities. Furthermore, they discovered a significant association between CFTRBD variants and symptoms of sinusitis and male infertility, but not overt lung disease as observed in CF, providing additional evidence of context-dependent dysfunction in humans.
Even though the medical community has been aware of the role of CFTR in pancreatitis, this study can improve the understanding of the overall spectrum of CF disease, as stated by Dr. Michael Boyle, director of the Johns Hopkins Adult Cystic Fibrosis Program in Baltimore.
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“The world now has a target for these patients with pancreatic problems to begin devising some ways to prevent their pancreas from destroying itself,” said Dr. David Whitcomb, co-senior investigator and chief of gastroenterology, hepatology and nutrition at the University of Pittsburgh School of Medicine.
“In the past, we would just watch people’s lives disintegrate or the pancreas disintegrate and have all kinds of problems. Now, we can start thinking about ways to intervene early and prevent the development of complex diseases.”
Identification of members of this new class of CFTR variants in symptomatic patients with a possible bicarbonate channelopathy can ultimately provide guidance for patient-specific clinical management. Furthermore, this discovery can drive the development of better drugs and also target better treatments for people with unexplained pancreatitis, an inflammation of the pancreas that can be life-threatening.
