Uromodulin is a glycoprotein that is encoded by the UMOD gene in humans. It is the most abundant protein in mammalian urine and is synthesized exclusively and abundantly in the cells of the thick ascending limb of Henle’s loop (TALH). The main function of Henle’s loop is to create hyperosmotic urine in relation to the osmotic situation in the blood.
Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin gene. UAKD summarizes several clinically defined diseases including medullary cystic kidney disease type 2 (MCKD2; OMIM #603860), familial juvenile hyperuricemic nephropathy (FJHN; OMIM #162000) and glomerulocystic kidney disease (GCKD; OMIM #609886). To date, more than 70 distinct UAKD-causing UMOD mutations are known. Although all mutations affect the UMOD gene, the clinical appearance is quite heterogeneous. Even patients carrying the same mutation develop different clinical symptoms.
Kemter and her colleagues identified a new mutant mouse line called UmodC93F. The mutation results in the disruption of a putative disulphide bond which is also absent in a known human UMOD mutation. The consequence of the disruption in the mouse Umod mutant is a dysfunction of thick ascending limb of Henle’s loop (TALH) cells of the kidney.
The UmodC93F was analysed in detail in the German Mouse Clinic as was before another mouse Umod mutant, namely UmodA227T. As expected, alterations directly connected to urine production were observed: the daily urine volume was increased in mutants compared with wild-type controls, urine osmolality was decreased and urine-to-plasma concentration ratios for sodium, potassium and chloride were significantly reduced.
The analysis of the skeleton by DXA method showed osteopenia – bone-mineral density and bone-mineral content were significantly decreased in 9-month-old heterozygous mutants of both genders. This finding is in accordance with clinical characteristics in human patients with UAKD.
Furthermore, the heterozygous mutant mice exhibited a reduced body weight (between 23-30%) at the age of nine months although the birth weight did not differ between wild-types and mutants. Fat mass was also strongly reduced (69-81%) in these animals.
The detailed knowledge of the phenotype of both Umod (UmodA227T and UmodC93F) mutant mouse lines identified a similar disease pathophysiology in both mutant mouse lines highly similar to UAKD in humans and, therefore, was a prerequisite to perform further detailed analysis of onset and speed of progression of renal dysfunction and morphological alterations in association of the particular Umod mutation itself and the zygosity status.
Taking together the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status. Detailed systemic phenotyping in the GMC including also extra-renal organ systems resulted in a recent further publication demonstrating single small additional effects associated with amino-acid-changing UMOD mutations (Kemter et al., PLOS one 8(10):e78337 (2013)).
Kemter, et al., Type of uromodulin mutation and allelic status influence onset and severity of uromodulinassociated kidney disease in mice, Human Molecular Genetics, 2013, Vol. 22, No. 20 4148–4163, doi:10.1093/hmg/ddt263