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Abstract Background The role of mutations in the serine protease inhibitor Kazal type 1 (<it>SPINK1</it>) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of <it>SPINK1 </it>mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore <it>SPINK1 </it>mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (<it>CASR</it>) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far. Methods We studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and <it>SPINK1 </it>(N34S) gene using melting curve analysis. Mutations within <it>CASR </it>gene were identified by DNA sequencing. Results A N34S <it>SPINK1 </it>mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the <it>CASR </it>gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein. Conclusion Mutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that <it>SPINK1 </it>mutations act as disease modifier and suggests an even more complex genetic model in <it>SPINK1 </it>related chronic pancreatitis.</p

A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations