Académie royale de Médecine de Belgique

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Résumé de Olivier Devuyst, membre associé

(Ont pris part à la discussion : MM. les Prs G. Vassart, L. Nguyen, L. Hue, J.E. Dumont, E. Pays, Th. Godfraind, G. Casimir, et A. Scheen).

FROM RARE DISEASES TO COMPLEX DISORDERS : THE CASE OF UROMODULIN

par Olivier Devuyst (UCL), membre associé.

Uromodulin (also named Tamm-Horsfall protein), the most abundant protein excreted in normal urine, is exclusively produced by the tubular cells lining the loop of Henle in the kidney. Studies on uromodulin knock-out mice demonstrated that uromodulin plays a protective role against urinary tract infections and kidney stones, and modulates the activity of transport systems mediating NaCl transport. Rare mutations in the UMOD gene that encodes uromodulin cause dominant disorders characterized by tubulo-interstitial fibrosis, alteration of urinary concentrating ability and progression to chronic kidney disease (CKD) during the second or third decade of life. The (mostly missense) mutations of uromodulin exert a gain-of-function effect, as indicated by the endoplasmic reticulum retention of mutant uromodulin in tubular cells. In addition to rare disorders associated with UMOD mutations, genome-wide association studies (GWAS) have shown that common variants in the UMOD locus are linked to an increased risk of CKD, hypertension and kidney stones in the general population. The deleterious variants (which are located in the promoter of UMOD) are associated with a 2-fold increase in the transcription and urinary secretion of uromodulin. Further studies based on cellular systems and transgenic Umod mice showed that these common variants are associated with a NaCl-sensitive hypertension and manifestations of premature kidney aging. Similar effects were observed in human subjects harbouring the deleterious UMOD variants. The high frequency of these risk variants (70-90% worldwide), combined with strong biological activity, suggests the action of a pathogen-driven selection at the UMOD locus. The studies summarized above provide the opportunity to investigate a spectrum of allelic effects for a gene involved in both rare diseases and frequent disorders like hypertension and CKD.