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Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

Bichet DG, El Tarazi A, Matar J, Lussier Y, Arthus MF, Lonergan M, Bockenhauer D, Bissonnette P - Clin Kidney J (2012)

Bottom Line: Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations.These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu.This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

View Article: PubMed Central - PubMed

Affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), Département de Physiologie, Université de Montréal, Montréal, Québec, Canada ; Centre de Recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.

ABSTRACT
It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a 'pure' type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

No MeSH data available.


Related in: MedlinePlus

A representation of the AQP2 protein and identification of 46 putative disease-causing AQP2 mutations. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular, transmembrane and cytoplasmic domains are defined according to Deen et al. [17]. Solid symbols indicate the location of the mutations (for references, view Table 1): M1I; L22V; V24A; L28P; G29S; A47V; Q57P; G64R; N68S; A70D; V71M; R85X; G100X; G100V; G100R; I107D; 369delC; T125M; T126M; A147T; D150E; V168M; G175R; G180S; C181W; P185A; R187C; R187H; A190T; G196D; W202C; G215C; S216P; S216F; K228E; R254Q; R254L; E258K and P262L. GenBank accession numbers—AQP2: AF147092, Exon 1; AF147093, Exons 2 through 4. NPA motifs and the N-glycosylation site are also indicated.
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fig3: A representation of the AQP2 protein and identification of 46 putative disease-causing AQP2 mutations. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular, transmembrane and cytoplasmic domains are defined according to Deen et al. [17]. Solid symbols indicate the location of the mutations (for references, view Table 1): M1I; L22V; V24A; L28P; G29S; A47V; Q57P; G64R; N68S; A70D; V71M; R85X; G100X; G100V; G100R; I107D; 369delC; T125M; T126M; A147T; D150E; V168M; G175R; G180S; C181W; P185A; R187C; R187H; A190T; G196D; W202C; G215C; S216P; S216F; K228E; R254Q; R254L; E258K and P262L. GenBank accession numbers—AQP2: AF147092, Exon 1; AF147093, Exons 2 through 4. NPA motifs and the N-glycosylation site are also indicated.

Mentions: To date, 46 putative disease-causing AQP2 mutations have been identified in 52 NDI families (Table 1 and Figure 3). AQP2 mutations in autosomal-recessive NDI, which are located throughout the gene, result in misfolded proteins that are retained in the endoplasmic reticulum (Table 1; Figure 3). In contrast, the dominant mutations reported to date are located in the region that codes for the carboxyl terminus of AQP2 [55]. Dominant AQP2 mutants form heterotetramers with wt-AQP2 and are misrouted [28, 36, 40, 45–48, 51–54]. Patients bearing these dominant mutations have a less severe phenotype as compared to patients who are compound heterozygotes or homozygotes for recessive mutations: the patient and her daughter first described to bear the AQP2-E258K-dominant mutation increased their urine osmolality to 350 mOsm/kg H2O following dDAVP [45]. Also the patient with a detailed phenotype described by Robertson and Koop [25] increased her urine osmolality to 220 mOsm/kg H2O during a mildly hypertonic dehydration, to 258 mOsm/kg H2O after dDAVP and to 305 mOsm/kg H2O after hydrochlorothiazide and indomethacin. This patient was found to be heterozygous for the R254Q mutation, possibly interfering with the S256 phosphorylation site [40]. In the mutant AQP2 (763–772) knockin mice, Sohara et al. [56] demonstrated a slight increase in urine osmolality following dehydration but a marked increase after the administration of Rolipram, a phosphodiesterase-4 inhibitor.


Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

Bichet DG, El Tarazi A, Matar J, Lussier Y, Arthus MF, Lonergan M, Bockenhauer D, Bissonnette P - Clin Kidney J (2012)

A representation of the AQP2 protein and identification of 46 putative disease-causing AQP2 mutations. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular, transmembrane and cytoplasmic domains are defined according to Deen et al. [17]. Solid symbols indicate the location of the mutations (for references, view Table 1): M1I; L22V; V24A; L28P; G29S; A47V; Q57P; G64R; N68S; A70D; V71M; R85X; G100X; G100V; G100R; I107D; 369delC; T125M; T126M; A147T; D150E; V168M; G175R; G180S; C181W; P185A; R187C; R187H; A190T; G196D; W202C; G215C; S216P; S216F; K228E; R254Q; R254L; E258K and P262L. GenBank accession numbers—AQP2: AF147092, Exon 1; AF147093, Exons 2 through 4. NPA motifs and the N-glycosylation site are also indicated.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4400507&req=5

fig3: A representation of the AQP2 protein and identification of 46 putative disease-causing AQP2 mutations. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular, transmembrane and cytoplasmic domains are defined according to Deen et al. [17]. Solid symbols indicate the location of the mutations (for references, view Table 1): M1I; L22V; V24A; L28P; G29S; A47V; Q57P; G64R; N68S; A70D; V71M; R85X; G100X; G100V; G100R; I107D; 369delC; T125M; T126M; A147T; D150E; V168M; G175R; G180S; C181W; P185A; R187C; R187H; A190T; G196D; W202C; G215C; S216P; S216F; K228E; R254Q; R254L; E258K and P262L. GenBank accession numbers—AQP2: AF147092, Exon 1; AF147093, Exons 2 through 4. NPA motifs and the N-glycosylation site are also indicated.
Mentions: To date, 46 putative disease-causing AQP2 mutations have been identified in 52 NDI families (Table 1 and Figure 3). AQP2 mutations in autosomal-recessive NDI, which are located throughout the gene, result in misfolded proteins that are retained in the endoplasmic reticulum (Table 1; Figure 3). In contrast, the dominant mutations reported to date are located in the region that codes for the carboxyl terminus of AQP2 [55]. Dominant AQP2 mutants form heterotetramers with wt-AQP2 and are misrouted [28, 36, 40, 45–48, 51–54]. Patients bearing these dominant mutations have a less severe phenotype as compared to patients who are compound heterozygotes or homozygotes for recessive mutations: the patient and her daughter first described to bear the AQP2-E258K-dominant mutation increased their urine osmolality to 350 mOsm/kg H2O following dDAVP [45]. Also the patient with a detailed phenotype described by Robertson and Koop [25] increased her urine osmolality to 220 mOsm/kg H2O during a mildly hypertonic dehydration, to 258 mOsm/kg H2O after dDAVP and to 305 mOsm/kg H2O after hydrochlorothiazide and indomethacin. This patient was found to be heterozygous for the R254Q mutation, possibly interfering with the S256 phosphorylation site [40]. In the mutant AQP2 (763–772) knockin mice, Sohara et al. [56] demonstrated a slight increase in urine osmolality following dehydration but a marked increase after the administration of Rolipram, a phosphodiesterase-4 inhibitor.

Bottom Line: Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations.These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu.This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

View Article: PubMed Central - PubMed

Affiliation: Groupe d'Étude des Protéines Membranaires (GÉPROM), Département de Physiologie, Université de Montréal, Montréal, Québec, Canada ; Centre de Recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Québec, Canada.

ABSTRACT
It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a 'pure' type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

No MeSH data available.


Related in: MedlinePlus