Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis
Abstract:Background & Aims
Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor, SPINK1, further incr… Show more
“…In a recent publication, Schneider et al (2011) investigated a large group of patients with "idiopathic" chronic pancreatitis and confirmed other studies that the combination of CFTR and serine protease inhibitor Kazaltype 1 (SPINK1) mutations markedly increase the risk of pancreatitis. However, a novel finding was that the variant R75Q of CFTR increases the risk of pancreatitis markedly.…”
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas.
“…In a recent publication, Schneider et al (2011) investigated a large group of patients with "idiopathic" chronic pancreatitis and confirmed other studies that the combination of CFTR and serine protease inhibitor Kazaltype 1 (SPINK1) mutations markedly increase the risk of pancreatitis. However, a novel finding was that the variant R75Q of CFTR increases the risk of pancreatitis markedly.…”
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas.
“…Individuals who carry only one allelic mutation of the CFTR gene still are at an increased risk of chronic pancreatitis three-to fourfold over the general population. Those individuals with heterozygous CFTR mutations typically have coexisting germline mutations in either SPINK1 or CTRC [38]. The CTRC gene carries a risk for chronic pancreatitis but usually in conjunction in individuals with mutations in either CFTR or SPINK1 [39].…”
Section: Gene (S) Involved Clinical Featuresmentioning
Pancreatic cancer is estimated to surpass breast cancer to become the third leading cause of cancer-related death in the USA in 2016. The 5-year overall survival is 7%, and most individuals are diagnosed with advanced disease. Thus, there is a need to improve the early detection of pancreatic cancer in order to detect and improve survival in the same way that mammograms and colonoscopies have improved survival for individuals with breast and colorectal cancer. This chapter discusses the genetics of hereditary pancreatic cancer, the current available screening options, and the use of biomarkers for early detection of pancreatic cancer.
“…However, group 2 variants can cause CFTR-related symptoms when present in trans in a group 1 variant in a compound heterozygous genotype. 4,5,[22][23][24][25][26] The partial damaging effects of group 2 variants on the CFTR gene product have been demonstrated in functional and biochemical analyses.…”
Section: Group 2 Cftr Variants Display Disease-contributing Potentialmentioning
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