Stop Codon Polymorphisms in the Human SLC9A1 Gene Disrupt or Compromise Na+/H+ Exchanger Function

The NHE1 isoform of the mammalian Na+/H+ exchanger is a ubiquitous plasma membrane protein that regulates intracellular pH in mammalian cells by removing one intracellular proton in exchange for one extracellular sodium. Deletion of the NHE1 gene (SLC9A1) affects the growth and motor ability of mice...

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Published in:PloS one 2016-09, Vol.11 (9), p.e0162902-e0162902
Main Authors: Li, Xiuju, Augustine, Aruna, Chen, Shuo, Fliegel, Larry
Format: Article
Language:English
Subjects:
Amino acids
Ataxia
Binding sites
Biochemistry
Biology and Life Sciences
Breast cancer
Cation Transport Proteins - genetics
Cation Transport Proteins - physiology
Cell Line
Clonal deletion
Codon, Terminator
Deoxyribonucleic acid
DNA
Gene deletion
Humans
Hydrogen
Intracellular
Kinases
Mammalian cells
Mammals
Medicine and Health Sciences
Membrane proteins
Mutagenesis
Mutants
Mutation
Na+/H+-exchanging ATPase
Nhe1 gene
Phosphorylation
Physical Sciences
Plasmids
Polymorphism, Genetic
Proteins
Regulation
Research and Analysis Methods
Rodents
Sodium
Sodium-Hydrogen Exchanger 1
Sodium-Hydrogen Exchangers - genetics
Sodium-Hydrogen Exchangers - physiology
Stop codon
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creator Li, Xiuju
Augustine, Aruna
Chen, Shuo
Fliegel, Larry
description The NHE1 isoform of the mammalian Na+/H+ exchanger is a ubiquitous plasma membrane protein that regulates intracellular pH in mammalian cells by removing one intracellular proton in exchange for one extracellular sodium. Deletion of the NHE1 gene (SLC9A1) affects the growth and motor ability of mice and humans but mutations and polymorphisms of the gene are only beginning to be characterized. NHE1 has a cytosolic C-terminal regulatory tail of approximately 315 amino acids and a 500 amino acid membrane domain. We examined the functional effects of three human stop codon mutations at amino acids 321, 449 and 735 in comparison with a mutant that had a shortened tail region (543 stop codon). The short mutants, 321, 449 and 543 stop codon mutant proteins, lost NHE1 activity and expression, and did not target to the plasma membrane. Protein for these short mutants was more rapidly degraded than the wild type and 735 ending proteins. The 735 terminating mutant, with the membrane domain and much of the cytosolic tail, had reduced protein expression and activity. The results demonstrate that early stop codon polymorphisms have significant and deleterious effects on the activity of the SLC9A1 protein product. The 735-NHE1 mutant, without the last 80 amino acids, had more minor defects. Surprisingly, retention of a proximal 43 amino acids adjacent to the membrane domain did little to maintain NHE1 expression, targeting and activity.
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Deletion of the NHE1 gene (SLC9A1) affects the growth and motor ability of mice and humans but mutations and polymorphisms of the gene are only beginning to be characterized. NHE1 has a cytosolic C-terminal regulatory tail of approximately 315 amino acids and a 500 amino acid membrane domain. We examined the functional effects of three human stop codon mutations at amino acids 321, 449 and 735 in comparison with a mutant that had a shortened tail region (543 stop codon). The short mutants, 321, 449 and 543 stop codon mutant proteins, lost NHE1 activity and expression, and did not target to the plasma membrane. Protein for these short mutants was more rapidly degraded than the wild type and 735 ending proteins. The 735 terminating mutant, with the membrane domain and much of the cytosolic tail, had reduced protein expression and activity. The results demonstrate that early stop codon polymorphisms have significant and deleterious effects on the activity of the SLC9A1 protein product. The 735-NHE1 mutant, without the last 80 amino acids, had more minor defects. 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Data curation: XL AA SC LF. Formal analysis: XL AA LF. Funding acquisition: LF. Investigation: XL AA SC. Methodology: XL AA LF. Resources: XL LF. Supervision: XL LF. Validation: XL AA SC LF. Visualization: XL AA LF. Writing – original draft: XL LF. Writing – review &amp; editing: XL AA SC LF.</notes><abstract>The NHE1 isoform of the mammalian Na+/H+ exchanger is a ubiquitous plasma membrane protein that regulates intracellular pH in mammalian cells by removing one intracellular proton in exchange for one extracellular sodium. Deletion of the NHE1 gene (SLC9A1) affects the growth and motor ability of mice and humans but mutations and polymorphisms of the gene are only beginning to be characterized. NHE1 has a cytosolic C-terminal regulatory tail of approximately 315 amino acids and a 500 amino acid membrane domain. We examined the functional effects of three human stop codon mutations at amino acids 321, 449 and 735 in comparison with a mutant that had a shortened tail region (543 stop codon). The short mutants, 321, 449 and 543 stop codon mutant proteins, lost NHE1 activity and expression, and did not target to the plasma membrane. Protein for these short mutants was more rapidly degraded than the wild type and 735 ending proteins. The 735 terminating mutant, with the membrane domain and much of the cytosolic tail, had reduced protein expression and activity. The results demonstrate that early stop codon polymorphisms have significant and deleterious effects on the activity of the SLC9A1 protein product. The 735-NHE1 mutant, without the last 80 amino acids, had more minor defects. Surprisingly, retention of a proximal 43 amino acids adjacent to the membrane domain did little to maintain NHE1 expression, targeting and activity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27636896</pmid><doi>10.1371/journal.pone.0162902</doi><oa>free_for_read</oa></addata></record>
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subjects Amino acids
Ataxia
Binding sites
Biochemistry
Biology and Life Sciences
Breast cancer
Cation Transport Proteins - genetics
Cation Transport Proteins - physiology
Cell Line
Clonal deletion
Codon, Terminator
Deoxyribonucleic acid
DNA
Gene deletion
Humans
Hydrogen
Intracellular
Kinases
Mammalian cells
Mammals
Medicine and Health Sciences
Membrane proteins
Mutagenesis
Mutants
Mutation
Na+/H+-exchanging ATPase
Nhe1 gene
Phosphorylation
Physical Sciences
Plasmids
Polymorphism, Genetic
Proteins
Regulation
Research and Analysis Methods
Rodents
Sodium
Sodium-Hydrogen Exchanger 1
Sodium-Hydrogen Exchangers - genetics
Sodium-Hydrogen Exchangers - physiology
Stop codon
title Stop Codon Polymorphisms in the Human SLC9A1 Gene Disrupt or Compromise Na+/H+ Exchanger Function
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