We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2.
These studies quantitatively show that the autosomal-dominant gene mutations responsible for UMOD-associated kidney disease cause a profound reduction of THP excretion.
These studies quantitatively show that the autosomal-dominant gene mutations responsible for UMOD-associated kidney disease cause a profound reduction of THP excretion.
Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life.
These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes.
These polymorphisms affect uromodulin concentration in the urine, and lower genetically determined urinary uromodulin concentrations seem to protect against renal disease.
Follow-up studies stimulated by findings from genome-wide association studies of kidney disease are already yielding promising results, such as the identification of an association between urinary uromodulin levels and incident CKD.
Genetic studies of urate transportation and of uromodulin-related nephropathy emphasize the pivotal importance of the proximal tubule in uric acid homeostasis.
Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease.
Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance.
In addition, approximately two-thirds of the known mutations lead to a cysteine amino acid change in uromodulin, and all such variants have been shown to cause UMOD-associated kidney disease.
We conclude that UMOD is unlikely to play a role in IgA nephropathy pathogenesis nor progression to end stage renal failure, and suggest that UMOD effects are restricted to some causes of renal disease, e.g. diabetes or hypertension.
In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Løken syndrome (n = 1).
In addition to causing specific UAKD, certain uromodulin gene polymorphisms have been linked to ESRD in general, suggesting that uromodulin plays a modulatory role in kidney disease progression.
In patients suffering from chronic tubulointerstitial nephropathy, hyperuricemia, and a low fractional excretion of uric acid mutation, analysis of the UMOD gene should be performed to diagnose UMOD-associated kidney disease.
UMOD-associated kidney disease has been proposed as a logical diagnostic label to replace FJHN, but given all these other mutations, an over-arching diagnostic term of 'autosomal dominant tubulointerstitial kidney disease' (ADTKD) has been recently adopted.