Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis?

[familial hypocalciuric hypercalcemia]

In 2003 we identified a family with familial hypocalciuric hypercalcemia (FHH ) (heterozygous CASR gene mutation L 173 P ) and a mutation in the pancreatic secretory trypsin inhibitor gene (SPINK 1 ) (N 34 S ). While family members with an isolated calcium-sensing receptor gene (CASR ) mutation remained healthy , a combination of the CASR and SPINK 1 gene mutation caused chronic pancreatitis (CP ). We thus speculate that the combination of two genetic defects affecting calcium homeostasis and pancreatic enzyme activation might represent a novel approach in chronic inherited pancreatic disease . We therefore sought to explore whether CASR gene mutations were prevalent in a cohort of patients with CP and confirmed SPINK 1 mutations .A cohort of 19 families (n =170 ) with a history of idiopathic CP (ICP ) was screened for mutations within the CASR gene ; 104 members of that cohort had a mutation (N 34 S ) within the SPINK 1 gene and 66 of those were suffering from CP . The entire CASR gene was screened for single strand conformation polymorphism under varying polyacrylamide gel conditions and subjected to direct dideoxy nucleotide sequencing of amplified cDNA .Single -strand conformation polymorphisms were observed in 59 samples , clustering of exons 3 , 4 and 7 . DNA sequence analysis revealed a yet unreported missense mutation in exon 7 (R 896 H ) and two conservative mutations in exon 4 (F 3 91 F ) and exon 7 (E 790 E ). Furthermore , an intronic polymorphism in nucleotide position 493 -19 G >A was detected in 19 out of 170 members of that cohort .We identified three novel calcium-sensing receptor gene mutations (1 missense mutation , 2 silent mutations and 1 intronic polymorphism ) in a cohort of 19 families with ICP . In particular , the kindred with the R 896 H mutation presenting with a similar pedigree to the family described above may indicate a role for CASR gene mutations in SPINK 1 -related CP . Again , only the patient with the combination of both CASR and N 34 S SPINK 1 gene mutation developed pancreatitis , whereas in the healthy parents and children only an isolated CASR or N 34 S SPINK 1 gene mutation could be detected . We suggest that the CASR gene is a novel yet undetected co -factor in a multifactorial genetic setting of SPINK 1 -related pancreatitis that alters the susceptibility for pancreatitis in these patients .

Diseases
Validation

Diseases presenting "pancreatitis" symptom

benign recurrent intrahepatic cholestasis

carcinoma of the gallbladder

cholangiocarcinoma

cystinuria

dracunculiasis

familial hypocalciuric hypercalcemia

scrub typhus

systemic capillary leak syndrome

This symptom has already been validated