title: Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone.
abstract: BACKGROUND
  A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members.
  
  
  METHODS
  Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone.
  
  
  RESULTS
  The mutation affects endoplasmic reticulum co-translational translocation and posttranslational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate.
  
  
  CONCLUSIONS
  A novel REN gene mutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.
authors.affiliation: Section on Nephrology, Wake Forest University School of Medicine, Winston- Salem, NC 27157, USA. ableyer@wfubmc.edu
authors.forename: A J
authors.initials: AJ
authors.lastname: Bleyer
authors.forename: M
authors.initials: M
authors.lastname: Zivná
authors.forename: H
authors.initials: H
authors.lastname: Hulková
authors.forename: K
authors.initials: K
authors.lastname: Hodanová
authors.forename: P
authors.initials: P
authors.lastname: Vyletal
authors.forename: J
authors.initials: J
authors.lastname: Sikora
authors.forename: J
authors.initials: J
authors.lastname: Zivný
authors.forename: J
authors.initials: J
authors.lastname: Sovová
authors.forename: T C
authors.initials: TC
authors.lastname: Hart
authors.forename: J N
authors.initials: JN
authors.lastname: Adams
authors.forename: M
authors.initials: M
authors.lastname: Elleder
authors.forename: K
authors.initials: K
authors.lastname: Kapp
authors.forename: R
authors.initials: R
authors.lastname: Haws
authors.forename: L D
authors.initials: LD
authors.lastname: Cornell
authors.forename: S
authors.initials: S
authors.lastname: Kmoch
authors.forename: P S
authors.initials: PS
authors.lastname: Hart
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000740:Anemia / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001706:Biopsy; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002648:Child; D002908:Chronic Disease; D012085:Chymosin; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004792:Enzyme Precursors; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use*; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000235:genetics; D006031:Glycosylation; D006579:Heterozygote; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics / Q000378:metabolism; D006994:Hypoaldosteronism / Q000235:genetics / Q000378:metabolism; D007671:Kidney Concentrating Ability / Q000235:genetics; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011141:Polyuria / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals / Q000235:genetics*; D021381:Protein Transport; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D004792:Enzyme Precursors; D021382:Protein Sorting Signals; C034675:preprorennin; D012083:Renin; D012085:Chymosin; D005438:Fludrocortisone