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Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)

Inborn mutations in the digestive protease carboxypeptidase A1 (CPA1) gene may be associated with hereditary and idiopathic chronic pancreatitis (CP). Pathogenic mutations, such as p.N256K, cause intracellular retention and reduced secretion of CPA1, accompanied by endoplasmic reticulum (ER) stress,...

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Autores principales: Sándor, Máté, Thiel, Franziska G., Schmid, Margit, Demcsák, Alexandra, Morales Granda, Nataly C., Németh, Balázs Csaba, Vajda, Sandor, Hoerning, André, Sahin-Tóth, Miklós
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779553/
https://www.ncbi.nlm.nih.gov/pubmed/36555104
http://dx.doi.org/10.3390/ijms232415463
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author Sándor, Máté
Thiel, Franziska G.
Schmid, Margit
Demcsák, Alexandra
Morales Granda, Nataly C.
Németh, Balázs Csaba
Vajda, Sandor
Hoerning, André
Sahin-Tóth, Miklós
author_facet Sándor, Máté
Thiel, Franziska G.
Schmid, Margit
Demcsák, Alexandra
Morales Granda, Nataly C.
Németh, Balázs Csaba
Vajda, Sandor
Hoerning, André
Sahin-Tóth, Miklós
author_sort Sándor, Máté
collection PubMed
description Inborn mutations in the digestive protease carboxypeptidase A1 (CPA1) gene may be associated with hereditary and idiopathic chronic pancreatitis (CP). Pathogenic mutations, such as p.N256K, cause intracellular retention and reduced secretion of CPA1, accompanied by endoplasmic reticulum (ER) stress, suggesting that mutation-induced misfolding underlies the phenotype. Here, we report the novel p.G250A CPA1 mutation found in a young patient with CP. Functional properties of the p.G250A mutation were identical to those of the p.N256K mutation, confirming its pathogenic nature. We noted that both mutations are in a catalytically important loop of CPA1 that is stabilized by the Cys248-Cys271 disulfide bond. Mutation of either or both Cys residues to Ala resulted in misfolding, as judged by the loss of CPA1 secretion and intracellular retention. We re-analyzed seven previously reported CPA1 mutations that affect this loop and found that all exhibited reduced secretion and caused ER stress of varying degrees. The magnitude of ER stress was proportional to the secretion defect. Replacing the naturally occurring mutations with Ala (e.g., p.V251A for p.V251M) restored secretion, with the notable exception of p.N256A. We conclude that the disulfide-stabilized loop of CPA1 is prone to mutation-induced misfolding, in most cases due to the disruptive nature of the newly introduced side chain. We propose that disease-causing CPA1 mutations exhibit abolished or markedly reduced secretion with pronounced ER stress, whereas CPA1 mutations with milder misfolding phenotypes may be associated with lower disease risk or may not be pathogenic at all.
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spelling pubmed-97795532022-12-23 Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1) Sándor, Máté Thiel, Franziska G. Schmid, Margit Demcsák, Alexandra Morales Granda, Nataly C. Németh, Balázs Csaba Vajda, Sandor Hoerning, André Sahin-Tóth, Miklós Int J Mol Sci Article Inborn mutations in the digestive protease carboxypeptidase A1 (CPA1) gene may be associated with hereditary and idiopathic chronic pancreatitis (CP). Pathogenic mutations, such as p.N256K, cause intracellular retention and reduced secretion of CPA1, accompanied by endoplasmic reticulum (ER) stress, suggesting that mutation-induced misfolding underlies the phenotype. Here, we report the novel p.G250A CPA1 mutation found in a young patient with CP. Functional properties of the p.G250A mutation were identical to those of the p.N256K mutation, confirming its pathogenic nature. We noted that both mutations are in a catalytically important loop of CPA1 that is stabilized by the Cys248-Cys271 disulfide bond. Mutation of either or both Cys residues to Ala resulted in misfolding, as judged by the loss of CPA1 secretion and intracellular retention. We re-analyzed seven previously reported CPA1 mutations that affect this loop and found that all exhibited reduced secretion and caused ER stress of varying degrees. The magnitude of ER stress was proportional to the secretion defect. Replacing the naturally occurring mutations with Ala (e.g., p.V251A for p.V251M) restored secretion, with the notable exception of p.N256A. We conclude that the disulfide-stabilized loop of CPA1 is prone to mutation-induced misfolding, in most cases due to the disruptive nature of the newly introduced side chain. We propose that disease-causing CPA1 mutations exhibit abolished or markedly reduced secretion with pronounced ER stress, whereas CPA1 mutations with milder misfolding phenotypes may be associated with lower disease risk or may not be pathogenic at all. MDPI 2022-12-07 /pmc/articles/PMC9779553/ /pubmed/36555104 http://dx.doi.org/10.3390/ijms232415463 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sándor, Máté
Thiel, Franziska G.
Schmid, Margit
Demcsák, Alexandra
Morales Granda, Nataly C.
Németh, Balázs Csaba
Vajda, Sandor
Hoerning, André
Sahin-Tóth, Miklós
Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title_full Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title_fullStr Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title_full_unstemmed Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title_short Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1)
title_sort novel p.g250a mutation associated with chronic pancreatitis highlights misfolding-prone region in carboxypeptidase a1 (cpa1)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779553/
https://www.ncbi.nlm.nih.gov/pubmed/36555104
http://dx.doi.org/10.3390/ijms232415463
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