scholarly journals The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

2012 ◽  
Vol 40 (5) ◽  
pp. 856-864 ◽  
Author(s):  
Tobias Hartmann ◽  
Mineko Terao ◽  
Enrico Garattini ◽  
Christian Teutloff ◽  
Joshua F. Alfaro ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Aldehyde Oxidase ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Impact

scholarly journals Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity

2015 ◽  
Vol 308 (9) ◽  
pp. C758-C766 ◽  
Author(s):  
Xinjun Cindy Zhu ◽  
Rafiquel Sarker ◽  
John R. Horton ◽  
Molee Chakraborty ◽  
Tian-E Chen ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Large Fraction ◽  
Regulatory Protein ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Single Nucleotide ◽  
Mutant Proteins ◽  
Homologous Protein ◽  
Genetic Abnormalities ◽  
The Impact

Genetic determinants appear to play a role in susceptibility to chronic diarrhea, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function.

The impact of human single nucleotide polymorphisms on Bacillus Calmette-Guérin responses

Vaccine ◽  
2020 ◽  
Vol 38 (40) ◽  
pp. 6224-6235
Author(s):  
Nicole L. Messina ◽  
Mihai G. Netea ◽  
Nigel Curtis
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Bacillus Calmette Guerin ◽  
Single Nucleotide ◽  
The Impact

The impact of single-nucleotide polymorphisms of human apurinic/apyrimidinic endonuclease 1 on specific DNA binding and catalysis

Biochimie ◽  
2019 ◽  
Vol 163 ◽  
pp. 73-83 ◽  
Author(s):  
Irina V. Alekseeva ◽  
Anastasiia T. Davletgildeeva ◽  
Olga V. Arkova ◽  
Nikita A. Kuznetsov ◽  
Olga S. Fedorova
Keyword(s):  
Dna Binding ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Impact

scholarly journals Single nucleotide polymorphisms in the human Na+-dicarboxylate cotransporter affect transport activity and protein expression

2010 ◽  
Vol 299 (4) ◽  
pp. F704-F711 ◽  
Author(s):  
Ana M. Pajor ◽  
Nina N. Sun
Keyword(s):  
Citric Acid ◽  
Single Nucleotide Polymorphisms ◽  
Citric Acid Cycle ◽  
Protein Abundance ◽  
Substrate Selectivity ◽  
Nucleotide Polymorphisms ◽  
Transport Activity ◽  
Single Nucleotide ◽  
Acid Cycle ◽  
The Impact

The sodium-coupled transport of citric acid cycle intermediates in the intestine and kidney is mediated by the Na+-dicarboxylate cotransporter, NaDC1. In the kidney, NaDC1 plays an important role in regulating succinate and citrate concentrations in the urine, which may have physiological consequences including the development of kidney stones. In the present study, the impact of nonsynonymous single nucleotide polymorphisms (SNPs) on NaDC1 expression and function was characterized using the COS-7 cell heterologous expression system. The I550V variant had an increased sensitivity to lithium inhibition although there were no significant effects on protein abundance. The L44F variant had no significant effects on expression or function. The membrane protein abundance of the M45L, V117I, and F254L variants was decreased, with corresponding decreases in transport activity. The A310P variant had decreased protein abundance as well as a change in substrate selectivity. The P385S variant had a large decrease in succinate transport Vmax, as well as altered substrate selectivity, and a change in the protein glycosylation pattern. The most damaging variant was V477M, which had decreased affinity for both succinate and sodium. The V477M variant also exhibited stimulation by lithium, indicating a change in the high-affinity cation binding site. We conclude that most of the naturally occurring nonsynonymous SNPs affect protein processing of NaDC1, and several also affect functional properties. All of these mutations are predicted to decrease transport activity in vivo, which would result in decreased intestinal and renal absorption of citric acid cycle intermediates.

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