Alternative titles; symbols
HGNC Approved Gene Symbol: AQP7
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:33,383,191-33,402,568 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | [Glycerol quantitative trait locus] | 614411 | Autosomal recessive | 3 |
Aquaporins are water channels that are usually found in tissues where water movements are abundant and/or physiologically important. High water permeability has been reported in mammalian sperm. To elucidate the molecular basis for the high water permeability of vertebrate sperm, Ishibashi et al. (1997) screened a rat testis library for additional members of the aquaporin gene family. They isolated a cDNA encoding AQP7, a predicted 269-amino acid protein. AQP7 contains the 6 transmembrane domains and intracellular N and C termini characteristic of aquaporins. Ishibashi et al. (1997) reported that the C terminus is exceptionally short, with very few hydrophilic residues. These authors also recovered a human AQP7 cDNA, and found that it had an identical stop site. Expression of rat AQP7 in Xenopus oocytes stimulated osmotic water permeability, as well as glycerol and urea transport. Characteristics of the water permeability of sperm of various vertebrate species were similar to those induced by AQP7: high water permeability with low activation energy, which was insensitive to mercury chloride. Northern blot analysis and in situ hybridization revealed that AQP7 is expressed abundantly in rat testis seminiferous tubules, in cells that appear to be late spermatids. This result was confirmed by immunohistochemistry, which showed that AQP7 is expressed during the late stages of spermatogenesis, and is localized on the plasma membrane of late spermatids.
In a systematic analysis of genes expressed in human adipose tissue, Kuriyama et al. (1997) identified AQP7L, a predicted 342-amino acid protein that putatively contains the 6 transmembrane domains and the NPA motif characteristic of aquaporins. On Northern blots, AQP7L is expressed predominantly in adipose tissue. Expression of AQP7L in Xenopus oocytes increased the coefficients of osmotic water permeability approximately 7-fold, and also facilitated the uptake of glycerol, suggesting that this aquaporin participates in glycerol transport in adipocytes. (Although Kuriyama et al. (1997) called this gene aquaporin-9 (AQP9), that designation has been given to the aquaporin gene discussed in entry 602914.)
Ishibashi et al. (1998) described the isolation of the mouse and the human AQP7 cDNA and the human AQP7 gene. The human AQP7 gene is identical with human adipose AQP (AQP7L). The deduced amino acid sequences of human and mouse AQP7 were 68% and 79% identical to those of rat AQP7, respectively. Mouse AQP7 is 67% identical to human AQP7. Such a lower conservation of AQP7 among species is unusual in the aquaporin family.
Ishibashi et al. (1998) determined that the human AQP7 gene is composed of 6 exons distributed over 6.5 kb. The exon/intron boundaries are identical to those of the human AQP3 gene (600170). The intron sizes are also similar.
Kondo et al. (2002) determined that the AQP7 gene contains 8 exons and spans about 18 kb. They identified an Alu repetitive sequence and binding sites for several different transcription factors within the AQP7 promoter, including multiple sites for CEBP (see 116897) and CREBP (see 123810). The AQP7 promoter also contains a putative peroxisome proliferator response element (PPRE) and a putative insulin (INS; 176730) response element (IRE). Mutation analysis demonstrated that the PPRE mediated induction of AQP7 promoter activity by a synthetic PPAR-gamma (PPARG; 601487) agonist and that the IRE mediated insulin-induced suppression of the AQP7 gene.
By fluorescence in situ hybridization, Ishibashi et al. (1998) assigned AQP7 to chromosome 9p13, where AQP3 is also localized, suggesting that 9p13 is the site of another aquaporin cluster. (AQP0 (154050), AQP2 (107777), AQP5 (600442), and AQP6 (601383) are colocalized at 12q13.)
Using radiation hybrid analysis, Kondo et al. (2002) mapped the AQP7 gene to chromosome 9p21.1-p13.3. They also identified 3 AQP7 pseudogenes.
The Fps1 gene in S. cerevisiae encodes a membrane protein that facilitates uptake of the metalloids arsenite and antimonite. Liu et al. (2002) examined the ability of the mammalian aquaglyceroporins Aqp7 and Aqp9 to substitute for the yeast Fps1 protein. The strain of S. cerevisiae in which Fps1 was deleted exhibited increased tolerance to arsenite and antimonite compared to a wildtype strain. Introduction of a plasmid containing rat Aqp9 reversed the metalloid tolerance of the deletion strain. Mouse Aqp7 was not expressed in yeast. The deletion strain showed reduced yeast transport of arsenite and antimonite, but uptake was enhanced by expression of Aqp9. Xenopus oocytes microinjected with either Aqp7 or Aqp9 cRNA exhibited increased transport of arsenite. These results suggested that AQP7 and AQP9 may be major routes of arsenite uptake into mammalian cells, an observation potentially important for understanding the action of arsenite as a human toxin and carcinogen, as well as its efficacy as a chemotherapeutic agent for acute promyelocytic leukemia.
Ceperuelo-Mallafre et al. (2007) noted that in animal studies aquaporin-7 is required for efflux of glycerol from adipocytes and influences whole-body glucose homeostasis. They tested the hypothesis that AQP7 gene expression levels may be affected by the presence of obesity and type 2 diabetes in humans. In their study of an obesity cohort (17 lean, 22 nonseverely obese, and 13 severely obese) and a type 2 diabetes cohort (17 lean and 39 obese), they found that severely obese women showed lower AQP7 expression levels compared with lean and nonseverely obese subjects (P less than 0.001). Circulating glycerol concentration was lower in severely obese subjects, but no correlation with AQP7 adipose tissue expression was observed.
Using specimens from 30 morbidly obese Spanish patients undergoing bariatric surgery, Miranda et al. (2009) analyzed AQP7 in subcutaneous and visceral adipose tissue and AQP9 in liver biopsies. Visceral adipose tissue AQP7 expression levels were significantly higher than in subcutaneous adipose tissue (p = 0.009). Subcutaneous adipose tissue AQP7 positively correlated with both visceral adipose tissue AQP7 and hepatic AQP9 mRNA expression (r = 0.44, p = 0.013 and r = 0.45, p = 0.012, respectively). The correlation between subcutaneous adipose tissue AQP7 and liver AQP9 was stronger in individuals who had glucose intolerance or type 2 diabetes (125853) (r = 0.602, p = 0.011). There was no difference in compartmental AQP7 adipose tissue distribution or AQP9 hepatic gene expression based on glucose tolerance classification. Miranda et al. (2009) concluded that there is coordinated regulation between adipose aquaglycoporins, with greater expression in visceral fat, and between subcutaneous adipose AQP7 and hepatic AQP9 gene expression in the context of morbid obesity.
Glycerol Quantitative Trait Locus
Kondo et al. (2002) found that a 48-year-old Japanese man who was homozygous for a missense mutation in the AQP7 gene (G264V; 602974.0001) exhibited greatly diminished glycerol release during exercise (GLYCQTL; 614411), despite a normal increase in plasma noradrenaline. Functional analysis in Xenopus oocytes showed that AQP7 with the G264V mutation could not transport glycerol or water. Kondo et al. (2002) noted that the normal adiposity and normal plasma glycerol level at rest in this individual suggested the existence of another pathway to maintain plasma glycerol in the resting state.
Ceperuelo-Mallafre et al. (2007) identified homozygosity for the G264V mutation in the AQP7 gene in an obese patient with type 2 diabetes (see 125853) who also had glycerol levels below the 10th percentile. The authors stated that the low-normal plasma glycerol levels in this patient supported the hypothesis of an alternative glycerol channel in adipocytes.
Body Mass Index Quantitative Trait Locus 17
Prudente et al. (2007) analyzed SNPs in the AQP7 gene in 977 Italian individuals (530 women and 447 men) and found association between a -953A-G promoter SNP (602972.0002) and body mass index (BMIQ17; 614411) in women; the association was confirmed in an independent case-control study of morbid obesity involving 299 women (odds ratio, 1.66; p = 0.04).
Hibuse et al. (2005) generated Aqp7 -/- mice and observed the development of adult-onset obesity in these mice, which had enlarged adipocytes exhibiting accumulation of triglycerides compared with wildtype mice. On a high-fat, high-sucrose diet, Aqp7 -/- mice developed obesity and insulin resistance even at a young age. Studies in Aqp7-knockout and -knockdown adipocytes revealed enhanced glycerol kinase (GK; 300474) activity. Hibuse et al. (2005) concluded that AQP7 disruption elevates adipose glycerol kinase activity, accelerates triglyceride synthesis in adipocytes, and leads to the development of obesity.
Hibuse et al. (2009) examined heart function and morphology in Aqp7-knockout mice under basal conditions and during pressure overload and analyzed cardiac glycerol consumption in ex vivo beating hearts. Cardiac morphology and function in knockout mice were similar to those of wildtype mice under basal conditions, although low glycerol and ATP content were observed in knockout hearts. Transfection studies in rat H9c2 cardiomyotubes showed that knockdown of Aqp7 was associated with a significant reduction of glycerol uptake. In ex vivo mouse hearts, cardiac glycerol consumption levels in knockout mice were significantly lower than those of wildtype mice. Isoproterenol challenge induced severe left ventricular hypertrophy in knockout mice, and transverse aortic constriction caused higher mortality in knockout than wildtype mice. Hibuse et al. (2009) concluded that AQP7 acts as a glycerol facilitator in cardiomyocytes and that glycerol is a substrate for cardiac energy production.
In a 48-year-old Japanese man who exhibited greatly diminished glycerol release during exercise (GLYCQTL; 614411) despite a normal increase in plasma noradrenaline, Kondo et al. (2002) identified homozygosity for a 963G-T transversion in exon 8 of the AQP7 gene, resulting in a gly264-to-val (G264V) substitution at a conserved residue in the sixth transmembrane domain. The man had a normal body mass index and normal plasma glucose level. Functional analysis in Xenopus oocytes showed that AQP7 with the G264V mutation could not transport glycerol or water.
In an obese (see 614411) Spanish patient with type 2 diabetes (see 125853) who also had glycerol levels below the 10th percentile, Ceperuelo-Mallafre et al. (2007) identified homozygosity for the G264V mutation in the AQP7 gene. In addition, 13 (7%) of 177 other individuals tested were heterozygous for G264V. There was no difference in distribution of the mutation between lean and obese individuals or between individuals with type 2 diabetes and nondiabetics.
Goubau et al. (2013) screened 3 unrelated children with psychomotor retardation of variable severity and hyperglyceroluria for AQP7 mutations. All 3 index patients were homozygous for the AQP7 G264V mutation; all had a subclinical platelet secretion defect which reduced ATP secretion, indicated by the absence of a secondary aggregation wave after epinephrine stimulation. Electron microscopy revealed round platelets with centrally located granules. Immunostaining showed AQP7 colocalization with dense granules, and immunoblot analysis detected release of AQP7 from platelets following stimulation with strong agonists. Three asymptomatic relatives carrying the homozygous G264V mutation showed hyperglyceroluria and platelet granule abnormalities on testing. Goubau et al. (2013) conclude that AQP7 is associated with urine glycerol levels and platelet secretion.
Prudente et al. (2007) analyzed SNPs in the AQP7 gene in 977 Italian individuals (530 women and 447 men) and found association between a -953A-G promoter SNP and increased body mass index (BMIQ17; see 614411) in women; the association was confirmed in an independent case-control study of morbid obesity involving 299 women (odds ratio, 1.66; p = 0.04). Functional studies showed that the -953G promoter had reduced transcriptional activity and impaired ability to bind CCAAT/enhancer binding protein-beta (CEBPB; 189965) transcription factor. In addition, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (p = 0.038).
Ceperuelo-Mallafre, V., Miranda, M., Chacon, M. R., Vilarrasa, N., Megia, A., Gutierrez, C., Fernandez-Real, J. M., Gomez, J. M., Caubet, E., Fruhbeck, G., Vendrell, J. Adipose tissue expression of the glycerol channel aquaporin-7 gene is altered in severe obesity but not in type 2 diabetes. J. Clin. Endocr. Metab. 92: 3640-3645, 2007. [PubMed: 17566090] [Full Text: https://doi.org/10.1210/jc.2007-0531]
Goubau, C., Jaeken, J., Levtchenko, E. N., Thys, C., Di Michele, M., Martens, G. A., Gerlo, E., De Vos, R., Buyse, G. M., Goemans, N., Van Geet, C., Freson, K. Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect. Genet. Med. 15: 55-63, 2013. [PubMed: 22899094] [Full Text: https://doi.org/10.1038/gim.2012.90]
Hibuse, T., Maeda, N., Funahashi, T., Yamamoto, K., Nagasawa, A., Mizunoya, W., Kishida, K., Inoue, K., Kuriyama, H., Nakamura, T., Fushiki, T., Kihara, S., Shimomura, I. Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. Proc. Nat. Acad. Sci. 102: 10993-10998, 2005. [PubMed: 16009937] [Full Text: https://doi.org/10.1073/pnas.0503291102]
Hibuse, T., Maeda, N., Nakatsuji, H., Tochino, Y., Fujita, K., Kihara, S., Funahashi, T., Shimomura, I. The heart requires glycerol as an energy substrate through aquaporin 7, a glycerol facilitator. Cardiovasc. Res. 83: 34-41, 2009. [PubMed: 19297367] [Full Text: https://doi.org/10.1093/cvr/cvp095]
Ishibashi, K., Kuwahara, M., Gu, Y., Kageyama, Y., Tohsaka, A., Suzuki, F., Marumo, F., Sasaki, S. Cloning and functional expression of a new water channel abundantly expressed in the testis permeable to water, glycerol, and urea. J. Biol. Chem. 272: 20782-20786, 1997. [PubMed: 9252401] [Full Text: https://doi.org/10.1074/jbc.272.33.20782]
Ishibashi, K., Yamauchi, K., Kageyama, Y., Saito-Ohara, F., Ikeuchi, T., Marumo, F., Sasaki, S. Molecular characterization of human aquaporin-7 gene and its chromosomal mapping. Biochim. Biophys. Acta 1399: 62-66, 1998. [PubMed: 9714739] [Full Text: https://doi.org/10.1016/s0167-4781(98)00094-3]
Kondo, H., Shimomura, I., Kishida, K., Kuriyama, H., Makino, Y., Nishizawa, H., Matsuda, M., Maeda, N., Nagaretani, H., Kihara, S., Kurachi, Y., Nakamura, T., Funahashi, T., Matsuzawa, Y. Human aquaporin adipose (AQPap) gene: genomic structure, promoter analysis and functional mutation. Europ. J. Biochem. 269: 1814-1826, 2002. [PubMed: 11952783] [Full Text: https://doi.org/10.1046/j.1432-1033.2002.02821.x]
Kuriyama, H., Kawamoto, S., Ishida, N., Ohno, I., Mita, S., Matsuzawa, Y., Matsubara, K., Okubo, K. Molecular cloning and expression of a novel human aquaporin from adipose tissue with glycerol permeability. Biochem. Biophys. Res. Commun. 241: 53-58, 1997. [PubMed: 9405233] [Full Text: https://doi.org/10.1006/bbrc.1997.7769]
Liu, Z., Shen, J., Carbrey, J. M., Mukhopadhyay, R., Agre, P., Rosen, B. P. Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc. Nat. Acad. Sci. 99: 6053-6058, 2002. [PubMed: 11972053] [Full Text: https://doi.org/10.1073/pnas.092131899]
Miranda, M., Ceperuelo-Mallafre, V., Lecube, A., Hernandez, C., Chacon, M. R., Fort, J. M., Gallart, L., Baena-Fustegueras, J. A., Simo, R., Vendrell, J. Gene expression of paired abdominal adipose AQP7 and liver AQP9 in patients with morbid obesity: relationship with glucose abnormalities. Metab. Clin. Exp. 58: 1762-1768, 2009. [PubMed: 19615702] [Full Text: https://doi.org/10.1016/j.metabol.2009.06.004]
Prudente, S., Flex, E., Morini, E., Turchi, F., Capponi, D., De Cosmo, S., Tassi, V., Guida, V., Avogaro, A., Folli, F., Maiani, F., Frittitta, L., Dallapiccola, B., Trischitta, V. A functional variant of the adipocyte glycerol channel aquaporin 7 gene is associated with obesity and related metabolic abnormalities. Diabetes 56: 1468-1474, 2007. [PubMed: 17351148] [Full Text: https://doi.org/10.2337/db06-1389]