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

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.

Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus

“…52 Interestingly, specific mutations direct AQP2 trafficking to distinct cellular compartments, such as the Golgi complex, 13 late endosomes and lysosomes 49 or the basolateral membrane. 51,53 These findings have provided insights into the intracellular trafficking motifs of AQP2.…”

“…The incidence of this type of congenital NDI might, however, be increased in populations with a high degree of consanguinity; we have found an over-representation of the Val71Met AQP2 allele in patients of Pakistani descent. 54 …”

Severe congenital nephrogenic diabetes insipidus in a compound heterozygote with a new large deletion of the AQP2 gene. A case report

“…By analogy with other autosomal recessive disorders, one can predict that the combination of mutations presented in each allele may also play a role in the phenotype variability and severity of NDI. On the other hand, 7 small deletions have been previously found in affected with severe features of NDI disease (Bichet et al, ; Sasaki et al, ). We described herein a novel exonic deletion (including exons 2, 3, and partially 4) as a recessive trait in a patient showing a severe phenotype of NDI.…”

“…Lack of function, often occurring through mistargeting of mutated proteins, induces NDI, a condition characterized by large urinary volumes. Autosomal recessive NDI is a rare disease usually seen in patient with consanguineous parents (Bichet et al, ; Sasaki, ; Wesche et al, ). Since most AQP2‐related NDI are found to be recessive hereditary traits (Robben, Knoers, & Deen, ), heterozygotes bearing one wild‐type form of the protein are usually nonsymptomatic as two defective alleles are required to induce the disease.…”

“…In addition, a minority of cases (up to seven), NDI results from small genomic deletions in the AQP2 (Bichet et al, ; García Castaño et al, ; Lieburg et al, ; Marr, Bichet, Lonergan et al, ; Moeller et al, ; Ohzeki, Igarashi, & Okamoto, ; Tajima, Okuhara, Satoh, Nakae, & Fujieda, ). However, no gross deletion was found at this time so ever: a deletion of G at nucleotide 721 (721delG), a deletion of 10 nucleotides starting at nucleotide 763 (763_772del), and a deletion of 7 nucleotides starting at nucleotide 812 (812_818del) (Bichet et al, ; Kuwahara et al, ; Sohara et al, ). In addition, a study by Park, Baik, Cheong, and Kang, () described a young Korean male with a compound heterozygous mutations located in exon 1.…”