Uromodulin kidney disease (UKD), caused by a mutation in the UMOD gene, is a rare inherited kidney disease that affects an estimated >5,000 individuals in the United States. In this inherited disease, affected individuals have one normal UMOD gene (that makes a normal gene product called uromodulin, and one abnormal UMOD gene that makes the mutant (abnormal) uromodulin. Affected individuals are often affected with gout at a young age and go on to develop kidney failure requiring dialysis or a kidney transplant. Within and between families, there is significant variation as to the age of kidney failure, rangin from 25 to 80 years. The cause of this variation is unclear. Recently, a small variation was found in the lead sequence (promoter) of the UMOD gene in the general population. This variation, present in 17% of the population, causes decreased production of uromodulin, the gene product of the UMOD gene. Similar to the general population, 17% of patients with UKD will also have the decreased production variant. For UKD patients, this variant could be found linked to the normal UMOD gene, resulting in decreased normal uromodulin production, or could be linked to the mutant UMOD gene, resulting in decreased production of the mutant uromodulin. The purpose of this study is to look at patients with UKD and correlate the presence of the UMOD variant with the age of kidney failure. The results of this study would be similar to a clinical tral where you give a medicine to decrease production of uromodulin. If the study shows that the variant associated with decreased production of uromodulin is also associated with a slower rate of progression of kidney failure, it is highly likely that maneuvers to lower uromodulin production (like a low salt diet or a blood pressure medicine called an angiotensin converting enzyme inhibitor) will also slow progression of the disease. Thus, this study could lead to an immediate treatment for this condition.
While each rare disease is uncommon, rare diseases affect almost one in ten members of the population. In the study of uromodulin kidney disease, we will study a gene variant that will lead us to a form of treatment for this disease. We believe this approach can then be used for many other diseases, even common ones in the population like high blood pressure, to point towards different types of treatment.
|Zikánová, Marie; Wahezi, Dawn; Hay, Arielle et al. (2018) Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females. Rheumatology (Oxford) 57:1180-1185|
|Lopes, L B; Abreu, C C; Souza, C F et al. (2018) Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease. Braz J Med Biol Res 51:e6560|
|Bleyer, Anthony J; Kidd, Kendrah; Živná, Martina et al. (2017) Autosomal Dominant Tubulointerstitial Kidney Disease. Adv Chronic Kidney Dis 24:86-93|
|Kim, Yeawon; Park, Sun-Ji; Manson, Scott R et al. (2017) Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease. JCI Insight 2:|
|Bleyer, Anthony J; Kmoch, Stanislav (2016) Tamm Horsfall Glycoprotein and Uromodulin: It Is All about the Tubules! Clin J Am Soc Nephrol 11:6-8|
|Bolar, Nikhita Ajit; Golzio, Christelle; Živná, Martina et al. (2016) Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. Am J Hum Genet 99:174-87|