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

Felderbauer, Peter; Klein, Wolfram; Bulut, Kerem; Ansorge, Nikolaus; Dekomien, Gabriele; Werner, Ilka; Epplen, Jörg T.; Schmitz, Frank; Schmidt, Wolfgang E.

doi:10.1080/00365520510024214

Cited by 73 publications

(41 citation statements)

References 18 publications

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“…A link between CaSR mutations and idiopathic epilepsy syndrome was established by multi-generational linkage analysis [7]. The involvement of CaSR mutations in predisposition to chronic pancreatitis and epilepsy were observed in patients without the characteristic derangements in serum calcium or parathyroid hormone [6,7] that are the signature of systemic Ca 2+ handling diseases, suggesting tissue-specific effects of these mutations.…”

Section: Introductionmentioning

confidence: 99%

“…CaSR is expressed in both the endocrine and exocrine pancreas [2], and mutations in CaSR [reviewed in 3,4] as well as the common polymorphism R990G [5] have been linked to pancreatitis in the absence [5] or presence of mutations in other genes predisposing to premature trypsin activation, e.g. SPINK1(N34S) [3,4,6]. A link between CaSR mutations and idiopathic epilepsy syndrome was established by multi-generational linkage analysis [7].…”

Section: Introductionmentioning

confidence: 99%

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Calcium Sensing Receptor Mutations Implicated in Pancreatitis and Idiopathic Epilepsy Syndrome Disrupt an Arginine-rich Retention Motif

Stepanchick

McKenna²,

McGovern

et al. 2010

Cell Physiol Biochem

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Calcium sensing receptor (CaSR) mutations implicated in familial hypocalciuric hypercalcemia, pancreatitis and idiopathic epilepsy syndrome map to an extended arginine-rich region in the proximal carboxyl terminus. Arginine-rich motifs mediate endoplasmic reticulum retention and/or retrieval of multisubunit proteins so we asked whether these mutations, R886P, R896H or R898Q, altered CaSR targeting to the plasma membrane. Targeting was enhanced by all three mutations, and Ca²⁺-stimulated ERK1/2 phosphorylation was increased for R896H and R898Q. To define the role of the extended arginine-rich region in CaSR trafficking, we independently determined the contributions of R890/R891 and/or R896/K897/R898 motifs by mutation to alanine. Disruption of the motif(s) significantly increased surface expression and function relative to wt CaSR. The arginine-rich region is flanked by phosphorylation sites at S892 (protein kinase C) and S899 (protein kinase A). The phosphorylation state of S899 regulated recognition of the arginine-rich region; S899D showed increased surface localization. CaSR assembles in the endoplasmic reticulum as a covalent disulfide-linked dimer and we determined whether retention requires the presence of arginine-rich regions in both subunits. A single arginine-rich region within the dimer was sufficient to confer intracellular retention comparable to wt CaSR. We have identified an extended arginine-rich region in the proximal carboxyl terminus of CaSR (residues R890 - R898) which fosters intracellular retention of CaSR and is regulated by phosphorylation. Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca²⁺ signaling characteristic of these diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calcium Sensing Receptor Mutations Implicated in Pancreatitis and Idiopathic Epilepsy Syndrome Disrupt an Arginine-rich Retention Motif

Stepanchick

McKenna²,

McGovern

et al. 2010

Cell Physiol Biochem

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“…Another mutation, P748P, was identified in two CP patients without SPINK1 N34S. Recently identified novel CASR mutations from Germany and India seen in exons 3 (P163R), 4 (L173P, F391F, I425S, D433H), 5 (V477A) and 7 (E870E, R896E) [8][9][10] were not observed in either patients or controls. Two intronic polymorphisms 493-94 C>T and 493-134 T>C included in exon 4 amplicon occurred with similar frequency in CP patients and controls, both with and without SPINK1 N34S polymorphisms.…”

Section: Resultsmentioning

confidence: 96%

“…Hypercalcemia itself has been associated with the development and complications of CP [2] . Recent studies from Germany and India have reported that novel calcium sensing receptor (CASR) gene mutations in combination with the presence of serine protease inhibitor Kazal 1type (SPINK1) N34S increased the risk of CP [8][9][10] . The SPINK1 N34S "high-risk haplotype" is strongly associated with CP, but only a limited portion of mutation carriers develop CP during their life time, suggesting that additional factors are necessary to develop this complex disorder [11,12] .…”

Section: Introductionmentioning

confidence: 99%

Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol

Muddana¹,

Lamb²,

Greer³

et al. 2008

WJG

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AIM:To test the hypothesis that calcium sensing receptor (CASR ) polymorphisms are associated with chronic pancreatitis (CP), and to determine whether serine protease inhibitor Kazal 1type (SPINK1 ) N34S or alcohol are necessary co-factors in its etiology. METHODS: Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms (SNPs) in exon 7 (A986S, R990G, and Q1011E). RESULTS:The CASR exon 7 R990G polymorphism was significantly associated with CP (OR, 2.01; 95% CI, 1.12-3.59; P = 0.015). The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption (OR, 3.12; 95% CI, 1.14-9.13; P = 0.018). There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected. CONCLUSION: Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.

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“…A combination of CASR and SPINK1 gene mutations has been proposed to predispose to idiopathic CP [67] . A study by Murugaian et al [68] identified 4 novel CASR mutations in TCP patients and concluded that the risk of disease may be further increased if there is an associated SPINK1 mutation.…”

Section: P R E V I O U S S T U D I E S W I T H S Y N T H E T I C S U mentioning

confidence: 99%

Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

Mahurkar¹,

Reddy²,

Rao³

et al. 2009

WJG

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Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies. Tropical calcific pancreatitis ( TCP) is a severe form of chronic pancreatitis unique to developing countries. With growing evidence of genetic factors contributing to the pathogenesis of TCP, this review is aimed at compiling the available information in this field. We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP.

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

Cited by 73 publications

References 18 publications

Calcium Sensing Receptor Mutations Implicated in Pancreatitis and Idiopathic Epilepsy Syndrome Disrupt an Arginine-rich Retention Motif

Calcium Sensing Receptor Mutations Implicated in Pancreatitis and Idiopathic Epilepsy Syndrome Disrupt an Arginine-rich Retention Motif

Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol

Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

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