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Scientists discover pancreatitis gene

Written by: Staff

Hyderabad, Apr 7 (UNI) Scientists at the Centre for Cellular and Molecular Biology (CCMB) and Asian Institute of Gastroenterology here have discovered a gene responsible for causing most cases of Tropical Calcific Pancreatitis that promises to lead to early identification and treatment of the disease.

Briefing reporters on the two-and-a-half year study which led to the finding of the gene, SPINK1, CCMB Director Lalji Singh said for over four decades, scientists had been grappling with complexities of Tropical Calcific Pancreatitis, which had high prevalence in tropical countries like India.

Dr Singh said the study found that SPINK1 produced a protein, which inhibited active trypsin inside pancreas.

A mutation in this gene might reduce the inhibitory function of the corresponding protein and the active trypsin within the pancreas might start digesting the very pancreas. They identified the same mutation in other types of chronic pancreatitis.

Involvement of this gene was different from the gene (cationic trypsinogen) implicated in other types of pancreatitis in the western population, he explained.

The research conducted abroad could not be extrapolated to the Indian population as it had a different genetic basis.

However, he cautioned the discovery of involvement of SPINK1 gene could not explain all cases of Tropical Calcific Pancreatitis.

The study found activation of trypsinogen inside the pancreas required a trigger to maintain constant supply of active trypsin in the pancreas. This process was known to be mediated by another protein-digesting enzyme Cathepsin B, a protein product of CTSB gene.

Cathepsin B and trypsinogens were normally stored in two dfferent compartments - lysosomes and zymogen granules respectively.

CCMB scientists thought that mutation in Cathepsin B gene might lead to its mislocalisation in zymogen granules instead of lysosomes, causing premature activation of trypsinogen, Dr Singh said.

Dr Chandak of CCMB and his colleagues sequenced this gene in over 300 Tropical Calcific Pancreatitis Patients and compared the results with 330 healthy individuals. They found replacement of a single base in the Cathepsin B gene, which changed amino acid leucine to valine in patients, compared to normal individuals.

They also found similar results in another group of patients in collaboration with Prof Varghese Thomas of Kozhikode, Kerala.

'Since the change of amino acid leucine to valine lies in the region of Cathepsin B, which is crucial for its transport, the mutation explains its co-localization with trypsinogen to zymogen granules, leading to premature activation of trypsinogen.

Cathepsin B gene may act as a susceptibility gene in the pathogenesis of Tropical Calcific Pancreatitis, irrespective of SPINK1 mutations.

'Thus, the discovery of involvement of Cathepsin B, the second candidate gene after SPINK1, that is likely to independently cause this disease is novel,' he added.

Dr Nageshwar Reddy of AIG said the discovery could result in accurate and early identification of the disease, genetic counselling to modify the course of disease and early treatment.

Pancreas stem cell transplants could also be explored in this area in future for treating the disease, he suggested.

Dr Chandak of CCMB felt the discovery might, on the basis of specific Cathepsin B variants, also explain occurrence of different types of Chronic Pancreatitis in patients without trypsinogen mutation, all over the world.

'As many of these patients are young and wage-earners for the family, early detection and modification of the course of the disease by appropriate counselling will be of tremendous help to patients and their families,' he added.

Cathepsin B has been sequenced by the CCMB scientists.

The results of the studies have been published in the prestigious online scientific journal 'Gut'.


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