title: A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue.
abstract: BACKGROUND
  Familial hyperaldosteronism type III (FH-III) is a rare and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K(+) channel 4 (Kir3.4), underlie the molecular basis of FH-III.
  
  
  OBJECTIVE
  The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation.
  
  
  METHODS
  We describe the case of a girl who came to medical attention at the age of 2 years because of polydipsia, polyuria, and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. Genomic DNA was isolated and KCNJ5 sequenced. Human adrenocortical cells were used as an in vitro model for the functional characterization of the mutant channel.
  
  
  RESULTS
  KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na(+)-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil.
  
  
  CONCLUSIONS
  Herein we report the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.
authors.affiliation: Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences (S.M., P.M., T.A.W.), University of Torino, Torino 10124 Italy; Medical Cell Biology (S.B., J.S.), University of Regensburg, 93053 Regensburg, Germany; Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (M.Z., C.A.S.), and Laboratory of Pathology (M.A., C.-C.R.L.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892; and Department of Inherited Endocrine Disorders (I.D., A.T.), Endocrinology Research Centre, Moscow 117036, Russia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.forename: Sascha
authors.initials: S
authors.lastname: Bandulik
authors.forename: Julia
authors.initials: J
authors.lastname: Stindl
authors.forename: Mihail
authors.initials: M
authors.lastname: Zilbermint
authors.forename: Ivan
authors.initials: I
authors.lastname: Dedov
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
authors.forename: Michael
authors.initials: M
authors.lastname: Allgaeuer
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Williams
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
mesh_terms: D002675:Child, Preschool; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics*; D009154:Mutation; D059606:Polydipsia / Q000235:genetics; D011141:Polyuria / Q000235:genetics
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels