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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

Pedigree of three Pakistani families referred to our laboratory each bearing the V71M AQP2 mutation (M). Family Aqp1 was first described by Langley [16]. Squares and circles represent male and female subjects, respectively, with unaffected individuals (open symbols), carriers (half-filled symbols) and affected individuals (solid symbol); n indicates normal allele. Haplotypes consist of markers that flank the AQP2 gene and that have been described previously [24]. The alleles bearing the individual mutations are identical suggesting a common ancestry.
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fig2: Pedigree of three Pakistani families referred to our laboratory each bearing the V71M AQP2 mutation (M). Family Aqp1 was first described by Langley [16]. Squares and circles represent male and female subjects, respectively, with unaffected individuals (open symbols), carriers (half-filled symbols) and affected individuals (solid symbol); n indicates normal allele. Haplotypes consist of markers that flank the AQP2 gene and that have been described previously [24]. The alleles bearing the individual mutations are identical suggesting a common ancestry.

Mentions: Of interest, in the first identification of AQP2 mutants by the Nijmegen group [17], the sequencing of the AQP2 gene in this isolated patient with autosomal-recessive diabetes insipidus followed a candidate gene approach guided by new understanding of the necessity, after vasopressin recognition and signaling, to insert water channels in the luminal membrane of principal cells of the collecting ducts to achieve water reabsorption [23]. We used the new sequencing data provided by Deen et al. to solve the molecular identification of NDI in two inbred Pakistani girls with non-X-linked NDI originally reported by Langley et al. [16]. They were found to be homozygous for the AQP2 V71M mutation, a recurrent mutation in Pakistani kindred since two other children from two other Pakistani families living in the UK, said to be unrelated, were found to bear the same mutation on the same AQP2 haplotype (Figure 2).


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)

Pedigree of three Pakistani families referred to our laboratory each bearing the V71M AQP2 mutation (M). Family Aqp1 was first described by Langley [16]. Squares and circles represent male and female subjects, respectively, with unaffected individuals (open symbols), carriers (half-filled symbols) and affected individuals (solid symbol); n indicates normal allele. Haplotypes consist of markers that flank the AQP2 gene and that have been described previously [24]. The alleles bearing the individual mutations are identical suggesting a common ancestry.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig2: Pedigree of three Pakistani families referred to our laboratory each bearing the V71M AQP2 mutation (M). Family Aqp1 was first described by Langley [16]. Squares and circles represent male and female subjects, respectively, with unaffected individuals (open symbols), carriers (half-filled symbols) and affected individuals (solid symbol); n indicates normal allele. Haplotypes consist of markers that flank the AQP2 gene and that have been described previously [24]. The alleles bearing the individual mutations are identical suggesting a common ancestry.
Mentions: Of interest, in the first identification of AQP2 mutants by the Nijmegen group [17], the sequencing of the AQP2 gene in this isolated patient with autosomal-recessive diabetes insipidus followed a candidate gene approach guided by new understanding of the necessity, after vasopressin recognition and signaling, to insert water channels in the luminal membrane of principal cells of the collecting ducts to achieve water reabsorption [23]. We used the new sequencing data provided by Deen et al. to solve the molecular identification of NDI in two inbred Pakistani girls with non-X-linked NDI originally reported by Langley et al. [16]. They were found to be homozygous for the AQP2 V71M mutation, a recurrent mutation in Pakistani kindred since two other children from two other Pakistani families living in the UK, said to be unrelated, were found to bear the same mutation on the same AQP2 haplotype (Figure 2).

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