Naturally occurring deletion mutants of the Pig-Specific, Intestinal crypt epithelial cell protein CLCA4b without Apparent Phenotype

Stephanie Plog, Nikolai Klymiuk, Stefanie Binder, Matthew Van Hook, Wallace B Thoreson, Achim D. Gruber, Lars Mundhenk

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The human CLCA4 (chloride channel regulator, calcium-Activated) modulates the intestinal phenotype of cystic fibrosis (CF) patients via an as yet unknown pathway. With the generation of new porcine CF models, species-specific differences between human modifiers of CF and their porcine orthologs are considered critical for the translation of experimental data. Specifically, the porcine ortholog to the human CF modulator gene CLCA4 has recently been shown to be duplicated into two separate genes, CLCA4a and CLCA4b. Here, we characterize the duplication product, CLCA4b, in terms of its genomic structure, tissue and cellular expression patterns as well as its in vitro electrophysiological properties. The CLCA4b gene is a pig-specific duplication product of the CLCA4 ancestor and its protein is exclusively expressed in small and large intestinal crypt epithelial cells, a niche specifically occupied by no other porcine CLCA family member. Surprisingly, a unique deleterious mutation of the CLCA4b gene is spread among modern and ancient breeds in the pig population, but this mutation did not result in an apparent phenotype in homozygously affected animals. Electrophysiologically, neither the products of the wild type nor of the mutated CLCA4b genes were able to evoke a calcium-Activated anion conductance, a consensus feature of other CLCA proteins. The apparently pig-specific duplication of the CLCA4 gene with unique expression of the CLCA4b protein variant in intestinal crypt epithelial cells where the porcine CFTR is also present raises the question of whether it may modulate the porcine CF phenotype. Moreover, the naturally occurring null variant of CLCA4b will be valuable for the understanding of CLCA protein function and their relevance in modulating the CF phenotype.

Original languageEnglish (US)
Article numbere0140050
JournalPloS one
Volume10
Issue number10
DOIs
StatePublished - Oct 16 2015

Fingerprint

intestinal crypts
cystic fibrosis
epithelial cells
Swine
Genes
Epithelial Cells
Phenotype
phenotype
Cystic Fibrosis
mutants
swine
Proteins
proteins
genes
Calcium
Chloride Channels
mutation
chloride channels
calcium
Modulators

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Naturally occurring deletion mutants of the Pig-Specific, Intestinal crypt epithelial cell protein CLCA4b without Apparent Phenotype. / Plog, Stephanie; Klymiuk, Nikolai; Binder, Stefanie; Van Hook, Matthew; Thoreson, Wallace B; Gruber, Achim D.; Mundhenk, Lars.

In: PloS one, Vol. 10, No. 10, e0140050, 16.10.2015.

Research output: Contribution to journalArticle

Plog, Stephanie ; Klymiuk, Nikolai ; Binder, Stefanie ; Van Hook, Matthew ; Thoreson, Wallace B ; Gruber, Achim D. ; Mundhenk, Lars. / Naturally occurring deletion mutants of the Pig-Specific, Intestinal crypt epithelial cell protein CLCA4b without Apparent Phenotype. In: PloS one. 2015 ; Vol. 10, No. 10.
@article{26e84a2cc22a41458d9d4e5f81de8251,
title = "Naturally occurring deletion mutants of the Pig-Specific, Intestinal crypt epithelial cell protein CLCA4b without Apparent Phenotype",
abstract = "The human CLCA4 (chloride channel regulator, calcium-Activated) modulates the intestinal phenotype of cystic fibrosis (CF) patients via an as yet unknown pathway. With the generation of new porcine CF models, species-specific differences between human modifiers of CF and their porcine orthologs are considered critical for the translation of experimental data. Specifically, the porcine ortholog to the human CF modulator gene CLCA4 has recently been shown to be duplicated into two separate genes, CLCA4a and CLCA4b. Here, we characterize the duplication product, CLCA4b, in terms of its genomic structure, tissue and cellular expression patterns as well as its in vitro electrophysiological properties. The CLCA4b gene is a pig-specific duplication product of the CLCA4 ancestor and its protein is exclusively expressed in small and large intestinal crypt epithelial cells, a niche specifically occupied by no other porcine CLCA family member. Surprisingly, a unique deleterious mutation of the CLCA4b gene is spread among modern and ancient breeds in the pig population, but this mutation did not result in an apparent phenotype in homozygously affected animals. Electrophysiologically, neither the products of the wild type nor of the mutated CLCA4b genes were able to evoke a calcium-Activated anion conductance, a consensus feature of other CLCA proteins. The apparently pig-specific duplication of the CLCA4 gene with unique expression of the CLCA4b protein variant in intestinal crypt epithelial cells where the porcine CFTR is also present raises the question of whether it may modulate the porcine CF phenotype. Moreover, the naturally occurring null variant of CLCA4b will be valuable for the understanding of CLCA protein function and their relevance in modulating the CF phenotype.",
author = "Stephanie Plog and Nikolai Klymiuk and Stefanie Binder and {Van Hook}, Matthew and Thoreson, {Wallace B} and Gruber, {Achim D.} and Lars Mundhenk",
year = "2015",
month = "10",
day = "16",
doi = "10.1371/journal.pone.0140050",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Naturally occurring deletion mutants of the Pig-Specific, Intestinal crypt epithelial cell protein CLCA4b without Apparent Phenotype

AU - Plog, Stephanie

AU - Klymiuk, Nikolai

AU - Binder, Stefanie

AU - Van Hook, Matthew

AU - Thoreson, Wallace B

AU - Gruber, Achim D.

AU - Mundhenk, Lars

PY - 2015/10/16

Y1 - 2015/10/16

N2 - The human CLCA4 (chloride channel regulator, calcium-Activated) modulates the intestinal phenotype of cystic fibrosis (CF) patients via an as yet unknown pathway. With the generation of new porcine CF models, species-specific differences between human modifiers of CF and their porcine orthologs are considered critical for the translation of experimental data. Specifically, the porcine ortholog to the human CF modulator gene CLCA4 has recently been shown to be duplicated into two separate genes, CLCA4a and CLCA4b. Here, we characterize the duplication product, CLCA4b, in terms of its genomic structure, tissue and cellular expression patterns as well as its in vitro electrophysiological properties. The CLCA4b gene is a pig-specific duplication product of the CLCA4 ancestor and its protein is exclusively expressed in small and large intestinal crypt epithelial cells, a niche specifically occupied by no other porcine CLCA family member. Surprisingly, a unique deleterious mutation of the CLCA4b gene is spread among modern and ancient breeds in the pig population, but this mutation did not result in an apparent phenotype in homozygously affected animals. Electrophysiologically, neither the products of the wild type nor of the mutated CLCA4b genes were able to evoke a calcium-Activated anion conductance, a consensus feature of other CLCA proteins. The apparently pig-specific duplication of the CLCA4 gene with unique expression of the CLCA4b protein variant in intestinal crypt epithelial cells where the porcine CFTR is also present raises the question of whether it may modulate the porcine CF phenotype. Moreover, the naturally occurring null variant of CLCA4b will be valuable for the understanding of CLCA protein function and their relevance in modulating the CF phenotype.

AB - The human CLCA4 (chloride channel regulator, calcium-Activated) modulates the intestinal phenotype of cystic fibrosis (CF) patients via an as yet unknown pathway. With the generation of new porcine CF models, species-specific differences between human modifiers of CF and their porcine orthologs are considered critical for the translation of experimental data. Specifically, the porcine ortholog to the human CF modulator gene CLCA4 has recently been shown to be duplicated into two separate genes, CLCA4a and CLCA4b. Here, we characterize the duplication product, CLCA4b, in terms of its genomic structure, tissue and cellular expression patterns as well as its in vitro electrophysiological properties. The CLCA4b gene is a pig-specific duplication product of the CLCA4 ancestor and its protein is exclusively expressed in small and large intestinal crypt epithelial cells, a niche specifically occupied by no other porcine CLCA family member. Surprisingly, a unique deleterious mutation of the CLCA4b gene is spread among modern and ancient breeds in the pig population, but this mutation did not result in an apparent phenotype in homozygously affected animals. Electrophysiologically, neither the products of the wild type nor of the mutated CLCA4b genes were able to evoke a calcium-Activated anion conductance, a consensus feature of other CLCA proteins. The apparently pig-specific duplication of the CLCA4 gene with unique expression of the CLCA4b protein variant in intestinal crypt epithelial cells where the porcine CFTR is also present raises the question of whether it may modulate the porcine CF phenotype. Moreover, the naturally occurring null variant of CLCA4b will be valuable for the understanding of CLCA protein function and their relevance in modulating the CF phenotype.

UR - http://www.scopus.com/inward/record.url?scp=84949525604&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949525604&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0140050

DO - 10.1371/journal.pone.0140050

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0140050

ER -