HGNC Approved Gene Symbol: AQP5
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:49,961,872-49,965,682 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Palmoplantar keratoderma, Bothnian type | 600231 | Autosomal dominant | 3 |
Aquaporin water channels, such as AQP5, play a fundamental role in transmembrane water movement in plant and animal tissues (see AQP1; 107776).
Since the molecular pathway by which water is secreted by salivary glands was unknown, Raina et al. (1995) isolated cDNA from rat submandibular gland by homology cloning. In vitro translation yielded a 27-kD polypeptide, and expression of the cRNA in Xenopus oocytes conferred a 20-fold increase in osmotic water permeability, which was reversibly inhibited by HgCl(2). Northern blot analysis demonstrated a 1.6-kb mRNA in submandibular, parotid, and sublingual salivary glands, lacrimal gland, eye, trachea, and lung. In situ hybridization demonstrated strong hybridization over the corneal epithelium of the eye and over the secretory lobules in salivary glands. This member of the mammalian aquaporin water channel family, designated AQP5, was implicated in the generation of saliva, tears, and pulmonary secretions.
Lee et al. (1996) isolated and characterized the human AQP5 cDNA and gene. The AQP5 cDNA from a human submaxillary gland library contained a 795-bp open reading frame encoding a 265-amino acid polypeptide. The deduced amino acid sequences of human and rat AQP5 are 91% identical, with 6 substitutions in the 22-amino acid COOH-terminal domain. Lee et al. (1996) identified a transcription initiation site 518 bp upstream of the initiating methionine.
By fluorescence in situ hybridization, Lee et al. (1996) mapped the AQP5 gene to chromosome 12q13. The AQP5 gene resides within a 7.4-kb SalI-EcoRI restriction fragment. The homologous mouse gene was localized to distal chromosome 15.
Lee et al. (1996) showed that microinjection of human AQP5 in Xenopus oocytes conferred mercurial-sensitive osmotic water permeability equivalent to other aquaporins.
Tsubota et al. (2001) examined the distribution of AQP5 in lacrimal gland biopsy specimens. Healthy controls and patients with either Mikulicz disease or non-Sjogren syndrome dry eye had the expected apical distribution of AQP5 in lacrimal acinar cells. Patients with Sjogren syndrome, however, had diffuse cytoplasmic staining for AQP5, with almost no labeling at the apical membrane. Sodium channel and sodium-potassium ATPase distribution were normal in all groups. Tsubota et al. (2001) concluded that there is a selective defect in lacrimal gland AQP5 trafficking in Sjogren syndrome that might contribute to decreased lacrimation and dry eye in these patients.
Sidhaye et al. (2006) observed a dose-responsive decrease in Aqp5 abundance in mouse lung epithelial cells exposed to hypotonic medium. Hypotonic reduction of Aqp5 was augmented and reduced, respectively, by conditions that activated or inhibited Trpv4 (605427). Hypotonic reduction of Aqp5 required extracellular calcium and was associated with increased intracellular calcium. The response to hypotonicity was recapitulated by coexpression of TRPV4 and AQP5 in human embryonic kidney cells. Sidhaye et al. (2006) concluded that AQP5 abundance is tightly controlled along a spectrum of extracellular osmolalities and that its abundance in hypotonic conditions can be regulated by TRPV4 activation.
By immunohistochemistry, Blaydon et al. (2013) observed strong localization of AQP5 to the plasma membrane in keratinocytes of the stratum granulosum. Levels of AQP5 in the palmar epidermis were much lower than those seen in cells of the sweat glands.
Tan et al. (2020) used comparative profiling of LGR5 (606667)+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. Tan et al. (2020) showed that stem cells within the AQP5+ compartment are a source of WNT (see 604663)-driven, invasive gastric cancer in vivo using Aqp5-creERT2 mouse models. Additionally, tumor-resident AQP5+ cells could selectively initiate organoid growth in vitro, which indicated that this population contains potential cancer stem cells. Tan et al. (2020) also found that in humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue.
Using linkage data in combination with exome sequencing followed by Sanger sequencing in families segregating autosomal dominant diffuse nonepidermolytic PPK (PPKB; 600231), Blaydon et al. (2013) identified heterozygosity for 5 different missense mutations in the AQP5 gene (600442.0001-600442.0005) in affected members of 7 Swedish families, 3 British families, and a Scottish family. The mutations all segregated with disease in the respective families and were not found in the dbSNP or 1000 Genomes Project databases. Immunohistochemical analyses revealed that the mutant AQP5 variants retained the ability to traffic to the plasma membrane; the analyses also showed an increase in levels of acetylated alpha-tubulin (see 602529) in a patient palm biopsy compared to a control palm, suggesting increased levels of microtubule stabilization in diffuse NEPPK palmar epidermis.
Ma et al. (2000) presented results from studies of Aqp5-null knockout mice indicating that AQP5 is responsible for the majority of water transport across the apical membrane of type I alveolar epithelial cells. The unimpaired alveolar fluid clearance in Aqp5-null mice indicated that high alveolar water permeability is not required for active, near-isosmolar fluid transport. King et al. (2000) stated that 5 aquaporin-null phenotypes had been reported: AQP0, AQP1, AQP2, AQP4, and AQP5.
Nejsum et al. (2002) studied the localization of AQPs 1 through 5 in rat and mouse skin and sweat glands and investigated the potential roles of AQPs in sweat secretion. The studies demonstrated that AQP5 resides in plasma membranes of sweat secretory cells and is essential for sweat secretion. Aqp5-null mice showed no apparent differences in the number or morphologic appearance of sweat glands. However, these mice showed a marked reduction in pilocarpine-induced sweat response. Nejsum et al. (2002) raised the possibility that dysregulation of AQP5 in sweat glands may contribute to the pathogenesis of hypohidrosis observed in patients with Sjogren syndrome (270150) who show markedly decreased sweating in response to methacholine stimulation. In contrast, hyperhidrosis (144110) is a chronic idiopathic disorder of excessive sweating which may affect the palms, axillae, soles, and face. They suggested that AQP5 inhibition may be a therapeutic option in these patients.
Two AQP water channels are expressed in mammalian cornea, AQP1 in endothelial cells and AQP5 in epithelial cells. Thiagarajah and Verkman (2002) examined the effect of Aqp1 or Aqp5 knockout in mice. Corneal thickness in fixed sections was reduced in Aqp1 null mice and increased in Aqp5 null mice. After exposure of the external corneal surface to hypotonic saline, the rate of corneal swelling was reduced by Aqp5 deletion. After exposure of the endothelial surface to hypotonic saline by anterior chamber perfusion, the rate of corneal swelling was reduced by Aqp1 deletion. The recovery of corneal transparency and thickness after hypotonic swelling was delayed in Aqp1 null mice. Thiagarajah and Verkman (2002) concluded that AQP1 and AQP5 provide the principal routes for corneal water transport across the endothelial and epithelial barriers, respectively.
In affected individuals of 7 Swedish families with Bothnian-type diffuse nonepidermolytic palmoplantar keratoderma (PPKB; 600231), including a family previously studied by Lind et al. (1994), Blaydon et al. (2013) identified heterozygosity for a c.113C-A transversion in exon 1 of the AQP5 gene, resulting in an ala38-to-glu (A38E) substitution at a residue located on the extracellular surface of the protein. The mutation segregated with disease in each family and was not found in the dbSNP or 1000 Genomes Project databases. Affected individuals carrying the A38E mutation all shared the same haplotype, indicating that A38E represents a founder mutation. In 1 of the Swedish families, however, most affected individuals carried a different missense mutation in AQP5 (R188C; 600442.0002); the A38E founder mutation was present in only 1 branch of the family and was inherited from an affected individual who married into the family.
In affected individuals of a Swedish family with Bothnian-type diffuse nonepidermolytic palmoplantar keratoderma (PPKB; 600231), Blaydon et al. (2013) identified heterozygosity for a c.562C-T transition in exon 3 of the AQP5 gene, resulting in an arg188-to-cys (R188C) substitution at a highly conserved residue lining the extracellular end of the water channel. The mutation, which was not found in the dbSNP or 1000 Genomes Project databases, segregated with disease in most of the family. In 1 branch of the family, however, affected individuals carried the A38E founder mutation (600442.0001), which was inherited from an affected individual who married into the family.
In affected individuals of 2 families of British descent with Bothnian-type diffuse nonepidermolytic palmoplantar keratoderma (PPKB; 600231), Blaydon et al. (2013) identified heterozygosity for a c.134T-G transversion in exon 1 of the AQP5 gene, resulting in an ile45-to-ser (I45S) substitution at a residue lining the extracellular end of the water channel. The mutation segregated with disease in both families and was not found in the dbSNP or 1000 Genomes Project databases.
In affected members of a large British family with Bothnian-type diffuse nonepidermolytic palmoplantar keratoderma (PPKB; 600231), Blaydon et al. (2013) identified heterozygosity for a c.529A-T transversion in exon 3 of the AQP5 gene, resulting in an ile177-to-phe (I177F) substitution at a residue lining the extracellular end of the water channel. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases.
In affected members of a family from Scotland with Bothnian-type diffuse nonepidermolytic palmoplantar keratoderma (PPKB; 600231), Blaydon et al. (2013) identified heterozygosity for a c.367A-G transition in exon 2 of the AQP5 gene, resulting in an asn123-to-asp (N123D) substitution at a residue located on the extracellular surface of the protein. The mutation segregated with disease in the family and was not found in the dbSNP or 1000 Genomes Project databases.
Blaydon, D. C., Lind, L. K., Plagnol, V., Linton, K. J., Smith, F. J. D., Wilson, N. J., McLean, W. H. I., Munro, C. S., South, A. P., Leigh, I. M., O'Toole, E. A., Lundstrom, A., Kelsell, D. P. Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am. J. Hum. Genet. 93: 330-335, 2013. [PubMed: 23830519] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.008]
King, L. S., Nielsen, S., Agre, P. Aquaporins and the respiratory system: advice for a lung investigator. J. Clin. Invest. 105: 15-16, 2000. [PubMed: 10619856] [Full Text: https://doi.org/10.1172/JCI9023]
Lee, M. D., Bhakta, K. Y., Raina, S., Yonescu, R., Griffin, C. A., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Preston, G. M., Agre, P. The human aquaporin-5 gene: molecular characterization and chromosomal localization. J. Biol. Chem. 271: 8599-8604, 1996. [PubMed: 8621489] [Full Text: https://doi.org/10.1074/jbc.271.15.8599]
Lind, L., Lundstrom, A., Hofer, P.-A., Holmgren, G. The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13. Hum. Molec. Genet. 3: 1789-1793, 1994. [PubMed: 7531539] [Full Text: https://doi.org/10.1093/hmg/3.10.1789]
Ma, T., Fukuda, N., Song, Y., Matthay, M. A., Verkman, A. S. Lung fluid transport in aquaporin-5 knockout mice. J. Clin. Invest. 105: 93-100, 2000. [PubMed: 10619865] [Full Text: https://doi.org/10.1172/JCI8258]
Nejsum, L. N., Kwon, T.-H., Jensen, U. B., Fumagalli, O., Frokiaer, J., Krane, C. M., Menon, A. G., King, L. S., Agre, P. C., Nielsen, S. Functional requirement of aquaporin-5 in plasma membranes of sweat glands. Proc. Nat. Acad. Sci. 99: 511-516, 2002. [PubMed: 11773623] [Full Text: https://doi.org/10.1073/pnas.012588099]
Raina, S., Preston, G. M., Guggino, W. B., Agre, P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J. Biol. Chem. 270: 1908-1912, 1995. [PubMed: 7530250] [Full Text: https://doi.org/10.1074/jbc.270.4.1908]
Sidhaye, V. K., Guler, A. D., Schweitzer, K. S., D'Alessio, F., Caterina, M. J., King, L. S. Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. Proc. Nat. Acad. Sci. 103: 4747-4752, 2006. [PubMed: 16537379] [Full Text: https://doi.org/10.1073/pnas.0511211103]
Tan, S. H., Swathi, Y., Tan, S., Goh, J., Seishima, R., Murakami, K., Oshima, M., Tsuji, T., Phuah, P., Tan, L. T., Wong, E., Fatehullah, A., and 11 others. AQP5 enriches for stem cells and cancer origins in the distal stomach. Nature 578: 437-443, 2020. [PubMed: 32025032] [Full Text: https://doi.org/10.1038/s41586-020-1973-x]
Thiagarajah, J. R., Verkman, A. S. Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling. J. Biol. Chem. 277: 19139-19144, 2002. [PubMed: 11891232] [Full Text: https://doi.org/10.1074/jbc.M202071200]
Tsubota, K., Hirai, S., King, L. S., Agre, P., Ishida, N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjogren's syndrome. Lancet 357: 688-689, 2001. [PubMed: 11247557] [Full Text: https://doi.org/10.1016/S0140-6736(00)04140-4]