Case Report
Autosomal Dominant Mutation in the Signal Peptide of Renin in a Kindred With Anemia, Hyperuricemia, and CKD

https://doi.org/10.1053/j.ajkd.2011.06.029Get rights and content

Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1β) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide.

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Case Report

We detected a novel heterozygous REN mutation in 1 of 39 kindreds (more information about patients and methods provided in Item S1, available as online supplementary material), indicating that heterozygous REN mutations are a rare cause of CKD with hyperuricemia and anemia. The novel REN mutation was a thymidine to cytosine change at position 28 of the REN complementary DNA (c.28T>C); this mutation lies within the first exon, which encodes the signal peptide, and corresponds to a tryptophan to

Discussion

The occurrence of anemia is surprising because kidney function in our patients initially was not profoundly decreased. Early onset of anemia also has been described by Živná et al8 in a 1-year-old affected child. Interestingly, when children advance to adolescence, anemia improves, with normal hemoglobin levels as long as kidney function is not too impaired.9 Increasing testosterone synthesis has been hypothesized to compensate for the childhood anemia,14 and the anemia is reported to respond

Acknowledgements

Support: This work was supported by a grant from the Maria Pesch Foundation Faculty of Medicine, University of Cologne, to Dr Beck, a National Institutes of Health grant (DK088767) to Dr Hildebrandt, and a grant from the Pediatric Scientist Development Program to Dr Wolf. Dr Hildebrandt is an investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and a F.G.L. Huetwell Professor.

Financial Disclosure: The authors declare that they have no relevant

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    Originally published online September 9, 2011.

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