Alternative titles; symbols
HGNC Approved Gene Symbol: AQP6
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:49,972,947-49,977,139 (from NCBI)
The aquaporins (AQPs) are a family of small integral membrane proteins related to the major intrinsic protein (MIP, or AQP0; 154050) of the lens. Ma et al. (1996) isolated a cDNA by degenerate PCR from a human kidney cDNA library that is related to AQP2 (107777). The predicted 282-amino acid AQP2L protein is 52% identical to AQP2 and 48% identical to MIP. The protein contains the conserved NPA (asn-pro-ala) motifs found in other MIP family members. Northern blots showed a 2.2-kb transcript only in kidney. When expressed in Xenopus oocytes, the protein was shown to increase water permeability in a mercurial-sensitive manner.
Yasui et al. (1999) showed that AQP6 is localized exclusively in intracellular membranes in renal epithelia. Sequential ultracentrifugation of rat kidney homogenates confirmed that AQP6 resides predominantly in vesicular fractions, and immunohistochemical and immunoelectron microscopic studies confirmed that more than 98% of AQP6 is located in intracellular membrane vesicles. In glomeruli, AQP6 is present in membrane vesicles within podocyte cell bodies and foot processes. In proximal tubules, AQP6 is also abundant in membrane vesicles within the subapical compartment of segment 2 and segment 3 cells, but was not detected in the brush border or basolateral membranes. In collecting duct, AQP6 resides in intracellular membrane vesicles in apical, mid, and basolateral cytoplasm of type A intercalated cells, but was not observed in the plasma membrane. Unlike other members of the AQP family, the unique distribution in intracellular membrane vesicles in multiple types of renal epithelia indicated that AQP6 is not simply involved in transcellular fluid absorption. These studies predicted that AQP6 participates in distinct physiologic function such as glomerular filtration, tubular endocytosis, and acid-base metabolism.
Ma et al. (1996) determined that the AQP2L gene has 4 exons and is organized similarly to MIP and AQP2. Transcription was shown to initiate 654 bp upstream of the first methionine. The gene appears to be single-copy by Southern blotting.
By PCR analysis of a panel of somatic cell hybrids, Ma et al. (1996) assigned the AQP2L gene to chromosome 12. They used fluorescence in situ hybridization to localize the gene to 12q13, the same band as MIP and AQP2.
Ma et al. (1997), who referred to this gene as aquaporin-6 (AQP6), demonstrated that, among the 7 human aquaporins cloned to that time (AQPs 0 to 6), the genes encoding the 4 most closely related aquaporins all mapped to 12q13: AQP0, AQP2, AQP5 (600442), and AQP6. To construct a physical map and identify novel aquaporin gene members of this cluster, Ma et al. (1997) screened a human CEPH B YAC library by PCR using primers derived from exon 4 of the AQP2 and AQP0 genes. A YAC clone with 200 kb of human DNA was isolated an analyzed. Primary pulsed field gel electrophoresis and Southern blot analysis indicated the presence of AQP2, AQP5, and AQP6 genes, but not AQP0. Restriction mapping and PCR analysis yielded a precise physical map in which the 3 aquaporin genes spanned only approximately 27 kb with the order, transcription orientation, and spacer length as follows: 5-prime--AQP2--5kb spacer--AQP5--7kb spacer--AQP6--3-prime.
Liu et al. (2005) stated that AQP6 is not a water channel but an anion-selective channel that functions by oscillating rapidly between closed and open states. They found that an asn60-to-gly substitution in rat Aqp6 eliminated the anion permeability of the channel when expressed in Xenopus oocytes, but it increased osmotic water permeability under basal conditions. Liu et al. (2005) concluded that the asparagine residue at the contact point between the second and fifth transmembrane domains in AQP6 may function as a teeter board needed for rapid structural oscillations during anion permeation.
Liu, K., Kozono, D., Kato, Y., Agre, P., Hazama, A., Yasui, M. Conversion of aquaporin 6 from an anion channel to a water-selective channel by a single amino acid substitution. Proc. Nat. Acad. Sci. 102: 2192-2197, 2005. [PubMed: 15671159] [Full Text: https://doi.org/10.1073/pnas.0409232102]
Ma, T., Yang, B., Kuo, W.-L., Verkman, A. S. cDNA cloning and gene structure of a novel water channel expressed exclusively in human kidney: evidence for a gene cluster of aquaporins at chromosome locus 12q13. Genomics 35: 543-550, 1996. [PubMed: 8812490] [Full Text: https://doi.org/10.1006/geno.1996.0396]
Ma, T., Yang, B., Umenishi, F., Verkman, A. S. Closely spaced tandem arrangement of AQP2, AQP5, and AQP6 genes in a 27-kilobase segment at chromosome locus 12q13. Genomics 43: 387-389, 1997. [PubMed: 9268644] [Full Text: https://doi.org/10.1006/geno.1997.4836]
Yasui, M., Kwon, T.-H., Knepper, M. A., Nielsen, S., Agre, P. Aquaporin-6: an intracellular vesicle water channel protein in renal epithelia. Proc. Nat. Acad. Sci. 96: 5808-5813, 1999. [PubMed: 10318966] [Full Text: https://doi.org/10.1073/pnas.96.10.5808]