Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9

• Published in: Human mutation Vol. 33; no. 8; pp. 1275 - 1284
• Main Authors: Chen, An-Ping, Chang, Min-Hwang, Romero, Michael F.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2012; Hindawi Limited
• Subjects: Animals; Antiporters - genetics; Biotinylation; Cl− channel; Electrophysiology; Female; Humans; intracellular pH; Mutagenesis, Site-Directed; Oocytes - metabolism; Polymorphism, Single Nucleotide - genetics; single nucleotide polymorphisms; SLC26A9; Sulfate Transporters; voltage clamp; Xenopus laevis; Xenopus oocytes
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22107

Slc26 anion transporters play crucial roles in transepithelial Cl− absorption and HCO3− secretion; Slc26 protein mutations lead to several diseases. Slc26a9 functions as a Cl− channel and electrogenic Cl−HCO3− exchanger, and can interact with cystic fibrosis transmembrane conductance regulator. Slc26a9(‐/‐) mice have reduced gastric acid secretion, yet no human disease is currently associated with SLC26A9 coding mutations. Therefore, we tested the function of nonsynonymous, coding, single nucleotide polymorphisms (cSNPs) of SLC26A9. Presently, eight cSNPs are NCBI documented: Y70N, T127N, I384T, R575W, P606L, V622L, V744M, and H748R. Using two‐electrode voltage‐clamp and anion selective electrodes, we measured the biophysical consequences of these cSNPs. Y70N (cytoplasmic N‐terminus) displays higher channel activity and enhanced Cl−HCO3− exchange. T127N (transmembrane) results in smaller halide currents but not for SCN−. V622L (STAS domain) and V744M (STAS adjacent) decreased plasma membrane expression, which partially accounts for decreased whole cell currents. Nevertheless, V622L transport is reduced to ∼50%. SLC26A9 polymorphisms lead to several function modifications (increased activity, decreased activity, altered protein expression), which could lead to a spectrum of pathophysiologies. Thus, knowing an individual's SLC26A9 genetics becomes important for understanding disease potentially caused by SLC26A9 mutations or modifying diseases, for example, cystic fibrosis. Our results also provide a framework to understand SLC26A9 transport modalities and structure–function relationships. Hum Mutat 33:1275–1284, 2012. © 2012 Wiley Periodicals, Inc.