Objective.In 2003 we identified a family with familial hypocalciuric hypercalcemia(FHH)(heterozygous CASR gene mutation L173P)and a mutation in the pancreatic secretory trypsin inhibitor gene(SPINK1)(N34S).While famil...Objective.In 2003 we identified a family with familial hypocalciuric hypercalcemia(FHH)(heterozygous CASR gene mutation L173P)and a mutation in the pancreatic secretory trypsin inhibitor gene(SPINK1)(N34S).While family members with an isolated calcium-sensing receptor gene(CASR)mutation remained healthy,a combination of the CASR and SPINK1 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 SPINK1 mutations.Material and methods.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(N34S)within the SPINK1 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.Results.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(R896H)and two conservative mutations in exon 4(F391F)and exon 7(E790E).Furthermore,an intronic polymorphism in nucleotide position 493-19 G > A was detected in 19 out of 170 members of that cohort.Conclusions.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 R896H mutation presenting with a similar pedigree to the family described above may indicate a role for CASR gene mutations in SPINK1-related CP.Again,only the patient with the combination of both CASR and N34S SPINK1 gene mutation developed pancreatitis,whereas in the healthy parents and展开更多
文摘Objective.In 2003 we identified a family with familial hypocalciuric hypercalcemia(FHH)(heterozygous CASR gene mutation L173P)and a mutation in the pancreatic secretory trypsin inhibitor gene(SPINK1)(N34S).While family members with an isolated calcium-sensing receptor gene(CASR)mutation remained healthy,a combination of the CASR and SPINK1 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 SPINK1 mutations.Material and methods.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(N34S)within the SPINK1 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.Results.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(R896H)and two conservative mutations in exon 4(F391F)and exon 7(E790E).Furthermore,an intronic polymorphism in nucleotide position 493-19 G > A was detected in 19 out of 170 members of that cohort.Conclusions.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 R896H mutation presenting with a similar pedigree to the family described above may indicate a role for CASR gene mutations in SPINK1-related CP.Again,only the patient with the combination of both CASR and N34S SPINK1 gene mutation developed pancreatitis,whereas in the healthy parents and
