Molecular genetics of renal disorders
Uromodulin (or Tamm-Horsfall protein) is the most abundant protein in normal urine, specifically produced in the kidney by epithelial cells of the thick ascending limb (TAL) of Henle’s loop. It plays a role in the protection against urinary tract infections (UTI) and renal stones, in salt handling in the TAL and in kidney innate immunity.
Mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), leading to renal damage and chronic kidney disease (CKD). The unit showed that uromodulin mutations lead to ER retention of mutant protein. This primary effect leads to ER stress, activation of the Unfolded Protein Response, and early induction of inflammation that likely is a key step in ADTKD-UMOD pathogenesis. Variants in UMOD are associated with risk of CKD and hypertension.
Through human, cellular and animal studies, this research group demonstrated the biological effect of UMOD risk variants, ie increase gene expression, and their causal link with salt- sensitive hypertension and to age-dependent renal damage. The group also showed that UMOD risk alleles have been likely kept at high frequency through evolution due to their protective effect against UTI.
The UMOD gene hence represents a paradigm of continuous genetic risk of disease, from rare mutations causing Mendelian disease to common alleles associated with complex traits. By studying molecular mechanisms our research has the final goal to identify novel therapeutic targets for renal disease and hypertension.
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Schaeffer C, Merella S, Pasqualetto E, Lazarevic D, Rampoldi L. Mutant uromodulin expression leads to altered homeostasis of the endoplasmic reticulum and activates the unfolded protein response. PLoS One. 2017 Apr 24;12(4):e0175970.
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Brunati M, Perucca S, Han L, Cattaneo A, Consolato F, Andolfo A, Schaeffer C, Olinger E, Peng J, Santambrogio S, Perrier R, Li S, Bokhove M, Bachi A, Hummler E, Devuyst O, Wu Q, Jovine L, Rampoldi L. The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin. Elife. 2015 Dec 17;4:e08887.
Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G, Glaudemans B, Laghmani K, Dell’Antonio G, the SKIPOGH team, Loffing J, Rastaldi MP, Manunta P, Devuyst O, Rampoldi L. Common noncoding UMOD variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 2013 Dec;19(12):1655-60.
Schaeffer C, Cattaneo A, Trudu M, Santambrogio S, Bernascone I, Giachino D, Caridi G, Campo A, Murtas C, Benoni S, Izzi C, De Marchi M, Amoroso A, Ghiggeri GM, Scolari F, Bachi A, Rampoldi L. Urinary secretion and extracellular aggregation of mutant uromodulin isoforms. Kidney Int. 2012 Apr;81(8):769-78.
Bernascone I, Janas S, Ikehata M, Trudu M, Corbelli A, Schaeffer C, Rastaldi MP, Devuyst O, Rampoldi L. A transgenic mouse model for uromodulin- associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure. Hum Mol Genet. 2010 Aug 1;19(15):2998-3010.
Bernascone I, Vavassori S, Di Pentima A, Santambrogio S, Lamorte G, Amoroso A, Scolari F, Ghiggeri GM, Casari G, Polishchuk R, Rampoldi L. Defective intracellular trafficking of uromodulin mutant isoforms. Traffic 2006 Nov;7(11):1567-79.