title: Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure.
abstract: Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.
authors: Center for Applied Genomics, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic.
authors: Martina
authors: M
authors: Zivná
authors: Helena
authors: H
authors: Hůlková
authors: Marie
authors: M
authors: Matignon
authors: Katerina
authors: K
authors: Hodanová
authors: Petr
authors: P
authors: Vylet'al
authors: Marie
authors: M
authors: Kalbácová
authors: Veronika
authors: V
authors: Baresová
authors: Jakub
authors: J
authors: Sikora
authors: Hana
authors: H
authors: Blazková
authors: Jan
authors: J
authors: Zivný
authors: Robert
authors: R
authors: Ivánek
authors: Viktor
authors: V
authors: Stránecký
authors: Jana
authors: J
authors: Sovová
authors: Kathleen
authors: K
authors: Claes
authors: Evelyne
authors: E
authors: Lerut
authors: Jean-Pierre
authors: JP
authors: Fryns
authors: P Suzanne
authors: PS
authors: Hart
authors: Thomas C
authors: TC
authors: Hart
authors: Jeremy N
authors: JN
authors: Adams
authors: Audrey
authors: A
authors: Pawtowski
authors: Maud
authors: M
authors: Clemessy
authors: Jean-Marie
authors: JM
authors: Gasc
authors: Marie-Claire
authors: MC
authors: Gübler
authors: Corinne
authors: C
authors: Antignac
authors: Milan
authors: M
authors: Elleder
authors: Katja
authors: K
authors: Kapp
authors: Philippe
authors: P
authors: Grimbert
authors: Anthony J
authors: AJ
authors: Bleyer
authors: Stanislav
authors: S
authors: Kmoch
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000740:Anemia / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000648:ultrastructure; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D012083:Renin