Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12

Uromodulin (UMOD), formerly known as the Tamm-Horsfall protein (1), is a glycoprotein with molecular weight 85 Kda. This protein is distributed in the body primarily within the kidney and is expressed by epithelial cells of the thick ascending limb of the Henle loop and by the distal convoluted tubules (2). UMOD is believed to have various regulatory functions in the kidney: it is responsible for the water impermeability of the tract of tubule in which it is expressed, and for urothelial defence against infections (3). In urine, this protein inhibits calcium salt aggregation, so could inhibit or oppose stone formation. The localization on chromosome 16p12 (where UMOD maps) of the second locus for autosomal dominant medullary cystic kidney disease (ADMCKD2) (4) drew our interest to molecular genetics of UMOD. Defects in the ability to concentrate urine, tubulo-interstitial infiltration and fibrosis with renal failure are typical clinical features of ADMCKD2: changes in concentrating ability and the tubulo-interstitial infiltration seem to be directly related to the UMOD functions. The ADMCKD2 region harbours SAH, another gene with primary renal expression, which encodes a 578 aminoacid residues polypeptide slightly homologous to bacterial acetyl-CoA synthase, whose role in hypertension has not yet been defined (5, 6). These assumptions led us to consider UMOD and SAH as the main candidate genes for ADMCKD2. Therefore, we set out to develop molecular analysis tools to detect mutations in these genes. These are also of interest for those who investigate these two kidney-specific genes.