Pancreatitis is a disease that causes the pancreas to become inflamed, triggering severe abdominal pain. Long-term pancreatitis can cause the organ to stop functioning altogether, leading to diabetes, and in many cases, pancreatic cancer. It is most often caused by alcohol abuse, but several forms are caused by genetic mutations. Several pancreatitis susceptibility genes have been identified to date. A relationship between a mutation in the cationic trypsinogen (PRSS1) gene and hereditary pancreatitis was first identified in 1996. Currently, HP has been defined as either two or more individuals within a family exhibiting pancreatitis for two or more generations, or pancreatitis linked to mutation of the PRSS1 gene. In 2000, a mutation in the serine protease inhibitor gene (SPINK1) was reported to be related to sporadic pancreatitis of unknown etiology. Patients with chronic pancreatitis (CP) due to SPINK1 gene mutation and chronic pancreatitits patients have a potentially high risk of pancreatic exocrine insufficiency, diabetes mellitus, and, of particular importance, pancreatic cancer.
The CFTR gene has been identified as a causative gene of cystic fibrosis, and it is also reported to be a gene associated with pancreatitis. About 1–4% of the overall cystic fibrosis population will have an episode of pancreatitis. The CFTR gene is considered to be a high-risk for developing pancreatitis when it is associated with other multiple mutations, especially SPINK1 gene mutations. Mutation causes a defect in the CFTR protein that causes abnormal bicarbonate transport, leading to defective pancreatic secretion. As a result of impaired pancreatic juice alkalinization and water secretion, protein plugs form in the pancreas and/or pancreatic duct. Aggregation may obstruct ducts and lead digestive enzymes to start injuring the surrounding tissues. Regarding the relationship with chronic pancreatitis, it has been reported that splicing efficiency and channel function decrease due to polymorphism on thymine bases, TG repeat polymorphism and Q1352H polymorphism. Some CFTR mutations can be inherited in a complex-type pattern.
Researchers from the University of Chicago and University of California, San Francisco discovered the cause of a new inherited form of pancreatitis. All began in 2012 when Mark Anderson, MD and PhD in Endocrinology at UCSF, saw a patient in his clinic with diabetes and pancreatitis. He explained that it ran in his family; in fact, they had been written up in a study for the Annals of Internal Medicine in 1968. Doctors at UCSF had documented 71 members of the family, then living in a farming community around Northern California. Of the 18 people they examined, six were officially diagnosed with pancreatitis and another five were suspected of having the disease. The particular form of pancreatitis affecting this family was especially severe and struck at a young age; children suffering from it were said to come inside from the fields and collapse onto the floor in pain. At the time, the researchers suspected that it was an autosomal dominant form of the disease, meaning that it could be inherited through one mutated gene. There was no way of proving this back then – before the advent of genetic sequencing – so the case was closed.
After Anderson and his colleagues realized the implications of their current patient’s connections to that story, they ordered genetic tests for her and several of her family members.Working together with Scott Oakes, MD, pathologist and cell biologist, they screened the family for the five known genetic mutations that can cause inherited pancreatitis. None of them matched, but a new mutation in a gene that produces a digestive enzyme called elastase 3B emerged as a possible culprit. In the lab, the researchers expressed both the normal and mutated forms of the elastase 3B gene, and used CRISPR gene-editing technology to engineer mice that had the mutation. They saw that the mutated form of the gene causes the pancreas to secrete too much of the enzyme, which damages the pancreas as it begins to digest itself. After 51 years, they had an answer for what was causing the unfortunate family’s misery. However, there are other potential candidates under current screening.
For example, one of them is another ion channel called TRPV6. This is a member of the transient receptor potential vanilloid ion channel superfamily. It promotes high calcium entry in absorptive and secretory tissues of mucosae and glands. It is mainly expressed in calcium -transporting epithelia. In the pancreas, TRPV6 expression is nearly 6-times higher in ductal cells than in acinar cells. More recently, Masamune et al. reported that impaired calcium uptake caused by TRPV6 variants was associated with early-onset chronic pancreatitis. Interestingly, 20% patients with functionally defective TRPV6 variants were trans-heterozygous for SPINK1 p.N34S as well, indicating that chronic pancreatitis in not relying on a single gene for its onset in the adult. Yet, is a complex multigenic disease, and a cumulative genetic handicap seems to be crucial for the development of the early-onset condition. Basically, it is not different from other current health conditions like heart diseases or cancer: genetic background prepares the terrain for the lifestyle to act.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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