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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) Immunofluorescence of AQP2 expressed in oocytes. Oocytes were not injected (1 control) or injected with either AQP2-wt (2, 1 ng), AQP2-D150E (3, 10 ng) or AQP2-G196D (4, 10 ng) messenger RNAs and incubated for 3 days prior to assay. Oocytes were immunostained and visualized with antibodies to AQP2. The injection process is represented in the right of the figure [21]. (b) Determination of water permeabilities (Pf) of wild-type (WT) AQP2 and mutants expressed in Xenopus oocytes. Oocytes were injected with either AQP2-wt (1 ng), AQP2-D150E (10 ng) or AQP2-G196D (10 ng) messenger RNAs and incubated for 2 days prior to assay. Determination of water permeabilities was performed by evaluation of volume increase in oocytes as induced by a 20-mosmol/kg H2O hypotonic shock [21].
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fig1: (a) Immunofluorescence of AQP2 expressed in oocytes. Oocytes were not injected (1 control) or injected with either AQP2-wt (2, 1 ng), AQP2-D150E (3, 10 ng) or AQP2-G196D (4, 10 ng) messenger RNAs and incubated for 3 days prior to assay. Oocytes were immunostained and visualized with antibodies to AQP2. The injection process is represented in the right of the figure [21]. (b) Determination of water permeabilities (Pf) of wild-type (WT) AQP2 and mutants expressed in Xenopus oocytes. Oocytes were injected with either AQP2-wt (1 ng), AQP2-D150E (10 ng) or AQP2-G196D (10 ng) messenger RNAs and incubated for 2 days prior to assay. Determination of water permeabilities was performed by evaluation of volume increase in oocytes as induced by a 20-mosmol/kg H2O hypotonic shock [21].

Mentions: Using dDAVP infusion studies and other families with severe polyuric characteristics in both male and female individuals, a non-X-linked form of NDI with a post-receptor (post-cAMP) defect was suggested [14–16]. A patient who presented shortly after birth with typical features of NDI but who exhibited normal coagulation and normal fibrinolytic and vasodilatory responses to dDAVP was shown to be a compound heterozygote for two missense mutations (R187C and S217P) in the AQP2 gene [17]. Expression of each of these two mutations in Xenopus oocytes revealed non-functional water channels. The oocytes of the African clawed frog Xenopus have provided a most useful test bed for looking at the functioning of many channel proteins. (See recent characterization of proteins with gain of function responsible for autosomal-dominant pseudohypoaldosteronism type II [18].) Oocytes are large cells about to become mature eggs ready for fertilization. They have all the normal translation machinery of living cells, so they will respond to the injection of messenger RNA by making the encoded protein [19]. This convenient expression system was key to the discovery of AQP1 by Agre [20] because frog oocytes have very low permeability and survive even in freshwater ponds. A representation of the injection process and expression of two AQP2 naturally occurring mutants responsible for autosomal-recessive NDI are described in Figure 1a. When subjected to a 20-mOsm osmotic shock, control oocytes have exceedingly low water permeability but test oocytes become highly permeable to water. These osmotic water permeability assays demonstrated an absence or very low water transport of the complementary RNA with AQP2 mutations (Figure 1b). Immunofluorescence and immunoblot studies demonstrated that these recessive mutants were retained in the endoplasmic reticulum [21, 22].


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) Immunofluorescence of AQP2 expressed in oocytes. Oocytes were not injected (1 control) or injected with either AQP2-wt (2, 1 ng), AQP2-D150E (3, 10 ng) or AQP2-G196D (4, 10 ng) messenger RNAs and incubated for 3 days prior to assay. Oocytes were immunostained and visualized with antibodies to AQP2. The injection process is represented in the right of the figure [21]. (b) Determination of water permeabilities (Pf) of wild-type (WT) AQP2 and mutants expressed in Xenopus oocytes. Oocytes were injected with either AQP2-wt (1 ng), AQP2-D150E (10 ng) or AQP2-G196D (10 ng) messenger RNAs and incubated for 2 days prior to assay. Determination of water permeabilities was performed by evaluation of volume increase in oocytes as induced by a 20-mosmol/kg H2O hypotonic shock [21].
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig1: (a) Immunofluorescence of AQP2 expressed in oocytes. Oocytes were not injected (1 control) or injected with either AQP2-wt (2, 1 ng), AQP2-D150E (3, 10 ng) or AQP2-G196D (4, 10 ng) messenger RNAs and incubated for 3 days prior to assay. Oocytes were immunostained and visualized with antibodies to AQP2. The injection process is represented in the right of the figure [21]. (b) Determination of water permeabilities (Pf) of wild-type (WT) AQP2 and mutants expressed in Xenopus oocytes. Oocytes were injected with either AQP2-wt (1 ng), AQP2-D150E (10 ng) or AQP2-G196D (10 ng) messenger RNAs and incubated for 2 days prior to assay. Determination of water permeabilities was performed by evaluation of volume increase in oocytes as induced by a 20-mosmol/kg H2O hypotonic shock [21].
Mentions: Using dDAVP infusion studies and other families with severe polyuric characteristics in both male and female individuals, a non-X-linked form of NDI with a post-receptor (post-cAMP) defect was suggested [14–16]. A patient who presented shortly after birth with typical features of NDI but who exhibited normal coagulation and normal fibrinolytic and vasodilatory responses to dDAVP was shown to be a compound heterozygote for two missense mutations (R187C and S217P) in the AQP2 gene [17]. Expression of each of these two mutations in Xenopus oocytes revealed non-functional water channels. The oocytes of the African clawed frog Xenopus have provided a most useful test bed for looking at the functioning of many channel proteins. (See recent characterization of proteins with gain of function responsible for autosomal-dominant pseudohypoaldosteronism type II [18].) Oocytes are large cells about to become mature eggs ready for fertilization. They have all the normal translation machinery of living cells, so they will respond to the injection of messenger RNA by making the encoded protein [19]. This convenient expression system was key to the discovery of AQP1 by Agre [20] because frog oocytes have very low permeability and survive even in freshwater ponds. A representation of the injection process and expression of two AQP2 naturally occurring mutants responsible for autosomal-recessive NDI are described in Figure 1a. When subjected to a 20-mOsm osmotic shock, control oocytes have exceedingly low water permeability but test oocytes become highly permeable to water. These osmotic water permeability assays demonstrated an absence or very low water transport of the complementary RNA with AQP2 mutations (Figure 1b). Immunofluorescence and immunoblot studies demonstrated that these recessive mutants were retained in the endoplasmic reticulum [21, 22].

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