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
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Diseases presenting "mutations in exon 4 (f391f) and exon 7" symptom

familial hypocalciuric hypercalcemia

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