title: Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene.
abstract: BACKGROUND
  Autosomal dominant pseudohypoaldosteronism type 1 (PHA1) is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (MR), but it is a matter of debate whether MR mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD) and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations.
  
  
  RESULTS
  We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products.
  
  
  CONCLUSIONS
  mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan. apricot_coco@yahoo.co.jp
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kanda
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.forename: Naoki
authors.initials: N
authors.lastname: Yokoyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morioka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Miwa
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hashimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaito
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D005260:Female; D006801:Humans; D007223:Infant; D009154:Mutation / Q000235:genetics*; D011546:Pseudohypoaldosteronism / Q000175:diagnosis* / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D018161:Receptors, Mineralocorticoid