Alternative titles; symbols
HGNC Approved Gene Symbol: AQP2
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:49,950,737-49,958,878 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Diabetes insipidus, nephrogenic, 2 | 125800 | Autosomal dominant; Autosomal recessive | 3 |
The AQP2 gene encodes an aquaporin-2 water channel located in the renal collecting tubules. Aquaporin-CHIP (AQP1; 107776) is located in the proximal renal tubule (Fushimi et al., 1993).
Fushimi et al. (1993) cloned the cDNA for the water channel of the apical membrane of the kidney collecting tubule in the rat. The gene shows 42% identity in amino acid sequence to AQP1. Expression in Xenopus oocytes markedly increased osmotic water permeability (Pf). The functional expression and the limited localization suggested that AQP2 is the vasopressin-regulated water channel. Fushimi et al. (1993) referred to AQP2 as WCH-CD, for 'water channel-collecting duct.'
Sasaki et al. (1993, 1994) cloned a cDNA for human AQP2 and found that it encodes a deduced protein with 91% amino acid identity to the rat protein. By screening kidney cDNA in cosmid libraries with a rat AQP2 cDNA probe, Deen et al. (1994) isolated human AQP2. They found that the predicted amino acid sequence shares 89.7% identity with the rat protein.
Nielsen et al. (1995) showed that arginine vasopressin (AVP; 192340) increases cellular water permeability by inducing exocytosis of AQP2-laden vesicles, transferring water channels from intracellular vesicles to the apical plasma membrane.
Using rat kidney slices and porcine kidney cells stably expressing rat Aqp2, Bouley et al. (2000) demonstrated that AQP2 trafficking can be stimulated by cAMP-independent pathways that utilize nitric oxide (NO). The NO donors sodium nitroprusside (SNP) and NONOate and the NO synthase (see 163731) substrate L-arginine mimicked the effect of vasopressin (VP), stimulating relocation of Aqp2 from cytoplasmic vesicles to the apical plasma membrane. SNP increased intracellular cGMP rather than cAMP, and exogenous cGMP stimulated AQP2 membrane insertion. Atrial natriuretic factor (108780), which signals via cGMP, also stimulated AQP2 translocation. Both the VP and SNP effects were blocked by a kinase inhibitor, and membrane insertion was blocked in cells expressing the phosphorylation-deficient mutant ser256 to ala, indicating that ser256 is required for signaling.
Kanno et al. (1995) reported that aquaporin-2 is detectable in the urine in both soluble and membrane-bound forms. In normal subjects, an infusion of desmopressin increased the urinary excretion of aquaporin-2. In 5 patients with central diabetes insipidus (CDI; 125700), administration of desmopressin increased urinary excretion of aquaporin-2; however, this response was not seen in 4 patients with X-linked (NDI1; 304800) or autosomal recessive nephrogenic diabetes insipidus (NDI2; 125800). Saito et al. (1997) determined that measuring urinary excretion of AQP2 is of value in diagnosing central diabetes insipidus. In normal subjects under ad libitum water drinking, urinary AQP2 was positively correlated with plasma arginine vasopressin levels, but not with urinary osmolality. Saito et al. (1997) found that measurement of AQP2 was also helpful when using a hypertonic saline infusion to diagnose CDI. Saito et al. (1999) investigated whether urinary excretion of AQP2 under ad libitum water intake was of value in the differentiation between psychogenic polydipsia and CDI. A 30-minute urine collection was made at 0900 hours in 3 groups: 11 patients with CDI (22 to 68 years old), 10 patients with psychogenic polydipsia (28 to 60 years old), and 15 normal subjects (21 to 38 years old). In the patients with CDI, the plasma arginine vasopressin level was low despite hyperosmolality, resulting in hypotonic urine. Urinary excretion of AQP2 was 37 +/- 15 fmol/mg creatinine, a value one-fifth less than that in the normal subjects. In the patients with psychogenic polydipsia, plasma arginine vasopressin and urinary osmolality were as low as those in the patients with CDI. However, urinary excretion of AQP2 of 187 +/- 45 fmol/mg creatinine was not decreased, and its excretion was equal to that in the normal subjects. The results indicated that urinary excretion of AQP2, under ad libitum water drinking, participates in the differentiation of psychogenic polydipsia from CDI.
Ishikawa et al. (2001) undertook to determine whether urinary excretion of AQP2 participates in the involvement of arginine vasopressin in hyponatremia less than 130 mmol/L in 33 elderly subjects more than 64 years of age during the last 5-year period. Plasma AVP levels remained relatively high despite hypoosmolality and were tightly linked with exaggerated urinary excretion of AQP2 and antidiuresis. Plasma AVP and urinary excretion of AQP2 were not reduced after an acute water load test. The inappropriate secretion of AVP was evident in the patients with the syndrome of inappropriate secretion of diuretic hormone (SIADH) and hypopituitarism, and hydrocortisone replacement normalized urinary excretion of AQP2 and renal water excretion in those with hypopituitarism. The authors concluded that urinary excretion of AQP2 may be a more sensitive measure of AVP effect on renal collecting duct cells than are plasma AVP levels, and that increased urinary excretion of AQP2 shows exaggerated AVP-induced antidiuresis in hyponatremic subjects in the elderly. In addition, mineralocorticoid-responsive hyponatremia of the elderly has to be carefully differentiated from SIADH in elderly subjects.
By in situ hybridization, Sasaki et al. (1993, 1994) mapped the AQP2 gene to chromosome 12q13, very close to the site of major intrinsic protein (MIP; 154050). The investigators suggested that a defect in the AQP2 gene is the basis of the autosomal form of nephrogenic diabetes insipidus (NDI2; 125800).
Deen et al. (1994) used fluorescence in situ hybridization to map the AQP2 gene to chromosome 12.
In a male patient with autosomal recessive nephrogenic diabetes insipidus (NDI2; 125800), Deen et al. (1994) identified compound heterozygosity for 2 mutations in the AQP2 gene (R187C, 107777.0001 and S216P, 107777.0002). Functional expression studies in Xenopus oocytes revealed that each mutation resulted in nonfunctional water channel proteins. Deen et al. (1995) found that expression of 3 mutant AQP2 proteins, R187C, S216P, and G64R (107777.0004), in Xenopus oocytes resulted in nonfunctional water channels. The transcripts encoding the missense AQPs were translated as efficiently as wildtype transcript and were equally stable. Immunocytochemistry demonstrated that the mutant AQP2 did not label in the plasma membrane. The authors proposed that the inability of the AQP2 proteins to facilitate water transport was caused by an impaired routing to the plasma membrane.
Missense mutations and a single-nucleotide deletion in the AQP2 gene were found by van Lieburg et al. (1994) in 3 NDI patients from consanguineous families (107777.0001; 107777.0004-107777.0005). Expression studies in Xenopus oocytes showed that the mutated AQP2 proteins were nonfunctional. Mulders et al. (1997) reported 3 additional NDI patients who were homozygous for mutations in the AQP2 gene. Functional expression studies showed that 2 of the mutations (107777.0006 and 107777.0007) resulted in functional proteins that were apparently retained in the endoplasmic reticulum and impaired in their routing to the plasma membrane.
In a study of a Dutch family with autosomal dominant NDI, Mulders et al. (1998) identified a mutation (107777.0009) in the AQP2 gene that exhibited a dominant-negative effect.
In affected members of 3 unrelated families with autosomal dominant NDI, Kuwahara et al. (2001) identified 3 different deletion mutations in exon 4 of the AQP2 gene (see, e.g., 107777.0014), all of which resulted in an elongated protein with a C-terminal tail of 61 amino acids. The predicted wildtype AQP2 protein contains 271 amino acids, whereas the predicted mutant proteins contained 330 to 333 amino acids because of the frameshift. In Xenopus oocytes injected with mutant AQP2 cRNAs, the osmotic water permeability was much smaller than that of oocytes with the AQP2 wildtype (14 to 17%). The results suggested that the trafficking of mutant AQP2 was impaired due to elongation of the C-terminal tail. The dominant-negative effect was attributed to oligomerization of the wildtype and mutant AQP2s. Marr et al. (2002) reported similar findings (see 107777.0015).
Carroll et al. (2006) identified the molecular basis of NDI in Arab families. Two novel missense mutations were identified in AQP2.
Yang et al. (2001) generated a mouse knockin model of NDI generated by targeted gene replacement with the thr126-to-met mutation (T126M; 107777.0007) along with mutations to preserve the consensus sequence for N-linked glycosylation found in human AQP2. The mutant mice died within 6 days after birth unless given supplemental fluid. Urine/serum analysis showed a urinary concentrating defect with serum hyperosmolality and low urine osmolality that could not be corrected by a V2 vasopressin agonist. Northern blot analysis revealed upregulated Aqp2-T126M transcripts identical in size to wildtype Aqp2. Immunoblot analysis indicated complex glycosylation of wildtype Aqp2 but endoglycosidase H-sensitive core glycosylation of the mutant, suggesting ER retention. Immunohistologic and histologic analyses revealed kidney collecting duct dilatation, papillary atrophy, and some plasma membrane Aqp2 expression. Yang et al. (2001) concluded that the Aqp2-T126M mutant creates a more severe phenotype than those observed in mice lacking water channels Aqp1, Aqp3 (600170), or Aqp4 (600308), and establishes a mouse model of human autosomal NDI.
Rojek et al. (2006) found that Aqp2-null mice appeared normal at birth but failed to thrive and died within 2 weeks of age. Kidneys from Aqp2-null pups showed papillary atrophy and signs of hydronephrosis. Mice with Aqp2 knockout targeted to the renal collecting ducts survived to adulthood, but they showed decreased body weight, 10-fold increased urine production, and decreased urinary osmolality and were unable to adapt to water deprivation. Rojek et al. (2006) concluded that AQP2 expression in kidney connecting tubules is sufficient for survival and that AQP2 expression in collecting ducts is required to regulate body water balance.
Congenital progressive hydronephrosis (cph) is a spontaneous recessive mutation that causes severe hydronephrosis and obstructive nephropathy in mice. McDill et al. (2006) found that homozygous cph mice were born at mendelian ratios and appeared grossly normal at birth, but they grew slowly and showed significant size and weight differences from postnatal day 8 onward. About 90% of cph mice died between 2 and 4 weeks of age. By 2 weeks, most had visibly enlarged abdomens and appeared lethargic. McDill et al. (2006) identified a ser256-to-leu (S256L) mutation in the Aqp2 gene as the cause of cph. The S256L substitution in the cytoplasmic tail of the Aqp2 protein prevented phosphorylation at S256 and the subsequent accumulation of Aqp2 on the apical membrane of the collecting duct principal cells. The interference with normal trafficking of Aqp2 by the S256L mutation resulted in a severe urine concentration defect. The NDI symptoms and the absence of developmental defects in the pyeloureteral peristaltic machinery before the onset of hydronephrosis suggested that the congenital obstructive nephropathy was likely the result of the polyuria.
In a male patient with nephrogenic diabetes insipidus (NDI2; 125800), Deen et al. (1994) identified compound heterozygosity for 2 mutations in the AQP2 gene: a 559C-T transition in exon 3, resulting in an arg187-to-cys (R187C) substitution, and a 646T-C transition in exon 4, resulting in a ser216-to-pro (S216P; 107777.0002) substitution. The former mutation was inherited from the father and the latter from the mother. Functional expression studies in Xenopus oocytes showed that both mutations resulted in a nonfunctional protein.
Van Lieburg et al. (1994) identified homozygosity for the R187C mutation in a Dutch patient with NDI. He was born of consanguineous parents; 3 other children in the family had died of severe dehydration and hypernatremia.
For discussion of the ser216-to-pro (S216) mutation in the AQP2 gene that was found in compound heterozygous state in a patient with nephrogenic diabetes insipidus (NDI2; 125800) by Deen et al. (1994), see 107777.0001.
In an Italian patient with nephrogenic diabetes insipidus (NDI2; 125800) whose parents were consanguineous, van Lieburg et al. (1994) identified a homozygous 190G-A transition in exon 1 of the AQP2 gene, resulting in a gly64-to-arg (G64R) substitution.
In a Palestinian patient with nephrogenic diabetes insipidus (NDI2; 125800) whose parents were consanguineous, van Lieburg et al. (1994) identified homozygosity for a 1-bp deletion (369delC) in the AQP2 gene, resulting in a frameshift and premature termination after amino acid 131.
In affected members of a consanguineous Austrian family with nephrogenic diabetes insipidus (NDI2; 125800), Mulders et al. (1997) identified a 533G-A transition in exon 2 of the AQP2 gene, resulting in an ala147-to-thr (A147T) substitution. The mutant AQP2 protein was functional when expressed in Xenopus oocytes, but was apparently impaired in its routing to the plasma membrane.
In affected members of a consanguineous family from Sri Lanka with nephrogenic diabetes insipidus (NDI2; 125800), Mulders et al. (1997) identified a 471C-T transition in exon 2 of the AQP2 gene, resulting in a thr126-to-met (T126M) substitution. The mutant AQP2 protein was functional when expressed in Xenopus oocytes, but was apparently impaired in its routing to the plasma membrane.
In affected members of a consanguineous Turkish family with nephrogenic diabetes insipidus (NDI2; 125800), Mulders et al. (1997) identified a 297A-G transition in exon 1 of the AQP2 gene, resulting in an asn68-to-ser (N68S) substitution. When expressed in oocytes, this mutant AQP2 was not functional because the substituted amino acid is part of the NPA box in loop B, which forms, together with a second NPA box in loop E, the most conserved amino acid sequence of the MIP-family.
Mulders et al. (1998) reported the first family in which nephrogenic diabetes insipidus segregated as an autosomal dominant trait (NDI2; 125800). An affected mother and daughter had a glu258-to-lys (E258K) mutation in the AQP2 gene. Functional expression studies showed that the mutant protein conferred only a small increase in water permeability, as a result of reduced expression at the plasma membrane. Coexpression of wildtype AQP2 with the E258K mutant revealed a dominant-negative effect on the water permeability conferred by wildtype AQP2. This effect was not seen when the wildtype protein was coexpressed with the AQP2 R187C mutant (107777.0001) in recessive NDI. The physiologically important phosphorylation of ser256 by protein kinase A was not affected by the E258K mutation. Immunoblot and microscopic analyses revealed that the E258K mutant was retained in the Golgi compartment. Since AQPs are thought to tetramerize, the retention of AQP2-E258K together with wildtype AQP2 in mixed tetramers in the Golgi compartment was a likely explanation for the dominant inheritance of NDI.
In Japanese female sibs with autosomal recessive nephrogenic diabetes insipidus (NDI2; 125800), Goji et al. (1998) identified compound heterozygosity for 2 mutations in the AQP2 gene: a 374C-T transition in exon 2, resulting in a thr125-to-met (T125M) substitution, and a 523G-A transition, resulting in a gly175-to-arg (G175R; 107777.0011) substitution. The water permeability of oocytes injected with wildtype complementary RNA increased 9.0-fold compared with the Pf of water-injected oocytes, whereas the increases in the Pf of oocytes injected with T125M and G175R RNA were only 1.7-fold and 1.5-fold, respectively. Immunoblot and immunocytochemistry indicated that the plasma membrane expressions of T125M and G175R AQP2 proteins were comparable to that of the wildtype, suggesting that although neither the T125M nor G175R mutation had a significant effect on plasma membrane expression, they distorted both the structure and function of the aqueous pore of AQP2. These results provided evidence that the NDI in patients with T125M and G175R mutations is attributable not to the misrouting of AQP2, but to the disrupted water channel function.
For discussion of the gly175-to-arg (G175R) mutation in the AQP2 gene that was found in compound heterozygous state in 2 sibs with autosomal recessive nephrogenic diabetes insipidus (NDI2; 125800) by Goji et al. (1998), see 107777.0010.
In a female patient with nephrogenic diabetes insipidus (NDI2; 125800), Canfield et al. (1997) identified compound heterozygosity for 2 mutations in the AQP2 gene: a leu22-to-val (L22V) substitution in exon 1, and a cys181-to-trp (C181W; 107777.0013) substitution in exon 3. The patient had symptoms dating from infancy. She responded to large doses of desmopressin, which decreased urine volume from 10 to 4 liters per day. Neither her parents nor her 3 sisters were polyuric. Residue cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near the NPA motif conserved in all aquaporins. Osmotic water permeability in Xenopus oocytes injected with cRNA encoding the mutant C181W AQP2 protein was not increased over water control, while expression of L22V cRNA increased the osmotic water permeability to approximately 60% of that for wildtype AQP2. Coinjection of the mutant cRNAs with the wildtype cRNA did not affect the function of the wildtype AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wildtype AQP2 showed endosome and plasma membrane staining. Canfield et al. (1997) concluded that AQP2 mutations can confer partially responsive nephrogenic diabetes insipidus.
For discussion of the cys181-to-trp (C181W) mutation in the AQP2 gene that was found in compound heterozygous state in a patient with nephrogenic diabetes insipidus (NDI2; 125800) by Canfield et al. (1997), see 107777.0012.
Kuwahara et al. (2001) identified a 1-bp deletion (721delG) in the AQP2 gene as a cause of autosomal dominant nephrogenic diabetes insipidus (NDI2; 125800). The mutation resulted in a frameshift and an elongated protein with a C-terminal tail of 61 additional amino acids. Elongation of the C-terminal tail resulted in impaired trafficking of the mutant AQP2, and a dominant-negative effect was observed.
In a 3-generation family with autosomal dominant inheritance of nephrogenic diabetes insipidus (NDI2; 125800), Marr et al. (2002) identified a 1-bp deletion (727delG) in the AQP2 gene. The predicted mutant protein had an altered and extended C-terminal tail. When expressed in renal epithelial cells, the mutant protein predominantly localized to the basolateral membrane and late endosomes/lysosomes, whereas wildtype AQP2 was expressed in the apical membrane. When coexpressed, wildtype AQP2 and AQP2-727G formed heterooligomers that mainly colocalized to late endosomes/lysosomes. The cells showed reduced water permeability due to reduced plasma membrane expression of wildtype AQP2. On the basis of their own data and the data of Kuwahara et al. (2001) (see 107777.0014), Marr et al. (2002) hypothesized that misrouting, rather than lack of function, may be a general mechanism for the 'loss of function' phenotype in dominant NDI.
In affected members from 2 Chinese families with nephrogenic diabetes insipidus (NDI2; 125800), Lin et al. (2002) identified compound heterozygosity for 2 mutations in exon 1 of the AQP2 gene: a 170A-C transversion, resulting in a gln57-to-pro (Q57P) substitution, and a 299G-T transversion, resulting in a gly100-to-val (G100V; 107777.0017) substitution. Expression of the Q57P and G100V AQP2 proteins showed an only 1.3-fold and 1.2-fold increase, respectively, in the water permeability in contrast to an 8.0-fold increase in oocytes injected with wildtype cRNA. The results provided evidence that the Q57P and G100V mutations in congenital nephrogenic diabetes insipidus are attributable to the misrouting of AQP2. The patients showed normal hypotensive and coagulation responses following the administration of desamino-8-D-arginine AVP, a clinical suggestion of normal vasopressin-2 receptors (V2R; 300538).
For discussion of the gly100-to-val (G100V) mutation in the AQP2 gene that was found in compound heterozygous state in affected individuals from 2 families with nephrogenic diabetes insipidus (NDI2; 125800) by Lin et al. (2002), see 107777.0016.
De Mattia et al. (2004) described 2 families with autosomal recessive nephrogenic diabetes insipidus (NDI2; 125800) in which affected individuals were compound heterozygous for a 785C-T transition in the AQP2 gene, resulting in a pro262-to-leu (P262L) substitution in the C-terminal tail, and either a 568G-A transition in the AQP2 gene, resulting in an ala190-to-thr (A190T; 107777.0019) substitution, or an R187C (107777.0001) substitution, respectively. Upon expression in oocytes, P262L AQP2 protein properly folded and was functional in contrast to the R187C and A190T proteins. In polarized epithelial cells, P262L protein was retained in intracellular vesicles and did not localize to the ER. Upon coexpression with wildtype AQP2, P262L protein interacted with wildtype AQP2, and the resulting heterotetramer properly localized to the apical membrane. De Mattia et al. (2004) concluded that P262L would act as a mutant in autosomal dominant NDI, except that its missorting is overruled by apical sorting of wildtype AQP2.
For discussion of the ala190-to-thr (A190T) mutation in the AQP2 gene that was found in compound heterozygous state in affected individuals from 2 families with nephrogenic diabetes insipidus (NDI2; 125800) by De Mattia et al. (2004), see 107777.0018.
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