Reviewer's report 
 A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis Title: 
in a family with heterozygous SPINK1 mutations 
 3  10 September 2003 Version: Date: 
 Joost P Drenth Reviewer: 
Reviewer's report: 
This version of the article by Peter Felderbauer has improved considerably over the first version. The 
points raised by both reviewers have been taken into account. While I see no hindrances against 
publication, the paper would still benefit from rigorous editing with respect to English usage. 
Minor comments 
The second gene that was characterized to be clearly associated with idiopathic chronic 
pancreatitis (ICP) was the cystic fibrosis transmembrane conductance regulator (CFTR) gene 
[10] and today more than 1000 CFTR mutations are reported The last part of the sentence “and today more than 1000 CFTR mutations are reported “does not add to the content of the paper. Please delete 
“The third ICP-associated gene that has been described, is the mutation of the serine protease 
inhibitor Kazal type 1 (SPINK1).” 
A gene is no mutation. Please shorten to The third ICP-associated gene that has been described, is 
serine protease inhibitor Kazal type 1 (SPINK1). 
“Moreover, the prevalence for N34S mutation lies in between 1.6 % (USA) [13], 1.58% (France) [14] 
and 0.36% 
(Germany) [12].” 
The prevalence in tested healthy controls stemming from these countries. 
Please reword: 
“Therefore mutations in proteins or even receptors regulating calcium homeostasis might 
represent novel pathogenetic risk factors for CP. At present, genetic defects resulting in chronic persistent hypercalcemia have not been reported to augment the risk for SPINK1 related CP. In the present study, we describe a family with a putative relationship between 
genetic defects in calcium homeostasis and SPINK1 mutations, suspected to cause CP.” 
(This is still unclear to me) 
To: 
Therefore, mutations in genes involved in calcium homeostasis might be associated with an 
increased risk for CP. We describe a family with members suffering from both CP and familial hypocalciuric hypercalcemia (FHH), and investigate the association of calcium sensing receptor gene (CASR) and SPINK1 mutations with CP. 
“and today more than 70 mutations in the CaR have been described [23].” 
Mutations occur in genes not in proteins 
“Moreover, it may provide new information about predisposing factors in SPINK1-related CP.” 
This sentence does not add anything new to the information given, please delete. 
“The presence of two putatively CP-related mutations makes our case unique.” 
Please delete, this does not give the reader substantial food for thought 
The authors mention that “If the CASR gene plays a more important role in SPINK1 related CP, will 
have to 
be evaluated in larger association studies” 
Are the authors aware of these studies, or have they performed these studies already in their 
laboratory? Could they lift the veil here?? 
Lastly, in this family their might or might not be an association between CASR mutation, SPINK1 
mutation and CP. We can never rule out that the observation occurred by chance. Nevertheless as stated before, it is an interesting observation. 
Reviewer's report 
 A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis Title: 
in a family with heterozygous SPINK1 mutations 
 3  10 September 2003 Version: Date: 
 Joost P Drenth Reviewer: 
Reviewer's report: 
This version of the article by Peter Felderbauer has improved considerably over the first version. The 
points raised by both reviewers have been taken into account. While I see no hindrances against 
publication, the paper would still benefit from rigorous editing with respect to English usage. 
Minor comments 
The second gene that was characterized to be clearly associated with idiopathic chronic 
pancreatitis (ICP) was the cystic fibrosis transmembrane conductance regulator (CFTR) gene 
[10] and today more than 1000 CFTR mutations are reported The last part of the sentence “and today more than 1000 CFTR mutations are reported “does not add to the content of the paper. Please delete 
“The third ICP-associated gene that has been described, is the mutation of the serine protease 
inhibitor Kazal type 1 (SPINK1).” 
A gene is no mutation. Please shorten to The third ICP-associated gene that has been described, is 
serine protease inhibitor Kazal type 1 (SPINK1). 
“Moreover, the prevalence for N34S mutation lies in between 1.6 % (USA) [13], 1.58% (France) [14] 
and 0.36% 
(Germany) [12].” 
The prevalence in tested healthy controls stemming from these countries. 
Please reword: 
“Therefore mutations in proteins or even receptors regulating calcium homeostasis might 
represent novel pathogenetic risk factors for CP. At present, genetic defects resulting in chronic persistent hypercalcemia have not been reported to augment the risk for SPINK1 related CP. In the present study, we describe a family with a putative relationship between 
genetic defects in calcium homeostasis and SPINK1 mutations, suspected to cause CP.” 
(This is still unclear to me) 
To: 
Therefore, mutations in genes involved in calcium homeostasis might be associated with an 
increased risk for CP. We describe a family with members suffering from both CP and familial hypocalciuric hypercalcemia (FHH), and investigate the association of calcium sensing receptor gene (CASR) and SPINK1 mutations with CP. 
“and today more than 70 mutations in the CaR have been described [23].” 
Mutations occur in genes not in proteins 
“Moreover, it may provide new information about predisposing factors in SPINK1-related CP.” 
This sentence does not add anything new to the information given, please delete. 
“The presence of two putatively CP-related mutations makes our case unique.” 
Please delete, this does not give the reader substantial food for thought 
The authors mention that “If the CASR gene plays a more important role in SPINK1 related CP, will 
have to 
be evaluated in larger association studies” 
Are the authors aware of these studies, or have they performed these studies already in their 
laboratory? Could they lift the veil here?? 
Lastly, in this family their might or might not be an association between CASR mutation, SPINK1 
mutation and CP. We can never rule out that the observation occurred by chance. Nevertheless as stated before, it is an interesting observation. 
Please review this paper.
user
Reviewer's report 
 A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis Title: 
in a family with heterozygous SPINK1 mutations 
 3  10 September 2003 Version: Date: 
 Joost P Drenth Reviewer: 
Reviewer's report: 
This version of the article by Peter Felderbauer has improved considerably over the first version. The 
points raised by both reviewers have been taken into account. While I see no hindrances against 
publication, the paper would still benefit from rigorous editing with respect to English usage. 
Minor comments 
The second gene that was characterized to be clearly associated with idiopathic chronic 
pancreatitis (ICP) was the cystic fibrosis transmembrane conductance regulator (CFTR) gene 
[10] and today more than 1000 CFTR mutations are reported The last part of the sentence “and today more than 1000 CFTR mutations are reported “does not add to the content of the paper. Please delete 
“The third ICP-associated gene that has been described, is the mutation of the serine protease 
inhibitor Kazal type 1 (SPINK1).” 
A gene is no mutation. Please shorten to The third ICP-associated gene that has been described, is 
serine protease inhibitor Kazal type 1 (SPINK1). 
“Moreover, the prevalence for N34S mutation lies in between 1.6 % (USA) [13], 1.58% (France) [14] 
and 0.36% 
(Germany) [12].” 
The prevalence in tested healthy controls stemming from these countries. 
Please reword: 
“Therefore mutations in proteins or even receptors regulating calcium homeostasis might 
represent novel pathogenetic risk factors for CP. At present, genetic defects resulting in chronic persistent hypercalcemia have not been reported to augment the risk for SPINK1 related CP. In the present study, we describe a family with a putative relationship between 
genetic defects in calcium homeostasis and SPINK1 mutations, suspected to cause CP.” 
(This is still unclear to me) 
To: 
Therefore, mutations in genes involved in calcium homeostasis might be associated with an 
increased risk for CP. We describe a family with members suffering from both CP and familial hypocalciuric hypercalcemia (FHH), and investigate the association of calcium sensing receptor gene (CASR) and SPINK1 mutations with CP. 
“and today more than 70 mutations in the CaR have been described [23].” 
Mutations occur in genes not in proteins 
“Moreover, it may provide new information about predisposing factors in SPINK1-related CP.” 
This sentence does not add anything new to the information given, please delete. 
“The presence of two putatively CP-related mutations makes our case unique.” 
Please delete, this does not give the reader substantial food for thought 
The authors mention that “If the CASR gene plays a more important role in SPINK1 related CP, will 
have to 
be evaluated in larger association studies” 
Are the authors aware of these studies, or have they performed these studies already in their 
laboratory? Could they lift the veil here?? 
Lastly, in this family their might or might not be an association between CASR mutation, SPINK1 
mutation and CP. We can never rule out that the observation occurred by chance. Nevertheless as stated before, it is an interesting observation. 
assistant