Journal Article

Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

Annie Michaud, Daniel Bur, Olivier Gribouval, Laurent Muller, Xavier Iturrioz, Maud Clemessy, Jean-Marie Gasc, Marie-Claire Gubler and Pierre Corvol

in Human Molecular Genetics

Volume 20, issue 2, pages 301-311
Published in print January 2011 | ISSN: 0964-6906
Published online October 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq465
Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

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Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized by persistent fetal anuria and perinatal death. During the systematic screening of mutations of the different genes of the renin–angiotensin system associated with RTD, two missense mutations in the renin gene were previously identified, the first affects one of the two catalytic aspartates (D38N) of renin, and the second, S69Y, is located upstream of the ‘flap', a mobile β-hairpin structure which covers the substrate-binding site of renin. Here we report a novel renin mutation leading to the duplication of the tyrosine residue Y15dup, homologous to Y9 in some other aspartyl proteases, which seems to play a crucial role along the activation pathway. The biochemical and cellular mechanisms underlying renin inactivation were investigated. We expressed prorenin constructs harboring the identified point mutations in two established cell lines, able (AtT-20 cells) or unable (CHO cells) to process prorenin to renin and we evaluated the cellular localization of renin mutants and their functional properties. All three mutants were misfolded to different levels, were enzymatically inactive and exhibited abnormal intracellular trafficking. We suggest a misfolding of Y15dup renin, a partial misfolding of D38N prorenin and a misfolding of S69Y prorenin leading to complete absence of secretion. The structural consequences of the renin mutations were estimated by molecular modeling, which suggested some important structural alterations. This is the first characterization of the mechanisms underlying loss of renin function in RTD.

Journal Article.  7144 words.  Illustrated.

Subjects: Genetics and Genomics

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