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Title: Dominant Renin Gene Mutations Associated with Early-Onset Hyperuricemia, Anemia, and Chronic Kidney Failure
Authors: Zivna, Martina ×
Hulkova, Helena
Matignon, Marie
Hodanova, Katerina
Vylet'al, Petr
Kalbacova, Marie
Baresova, Veronika
Sikora, Jakub
Blazkova, Hana
Zivny, Jan
Ivanek, Robert
Stranecky, Viktor
Sovova, Jana
Claes, Kathleen
Lerut, Evelyne
Fryns, Jean-Pierre
Hart, P. Suzanne
Hart, Thomas C
Adams, Jeremy N
Pawtowski, Audrey
Clemessy, Maud
Gasc, Jean-Marie
Guebler, Marie-Claire
Antignac, Corinne
Elleder, Milan
Kapp, Katja
Grimbert, Philippe
Bleyer, Anthony J
Kmoch, Stanislav #
Issue Date: Aug-2009
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:85 issue:2 pages:204-213
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.
URI: 
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Cell & Tissue Research
Department of Human Genetics - miscellaneous
Laboratory of Nephrology
× corresponding author
# (joint) last author

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