Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease

Abstract

SummaryBackground and objectives Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by uromodulin (UMOD) gene mutations. This study explored genotype-phenotype correlations by examining the relationship between the type of UMOD mutation and the age at onset of ESRD.Design, setting, participants & measurements Extensive bibliographic research was used to ascertain patient-level data of all patients with UAKD published up to October 2011. Data included sex; ages at onset of hyperuricemia, gout, and ESRD; and UMOD genotype. Kaplan-Meier analysis and Cox proportional hazards models fitted with shared gamma frailty terms to adjust for within-family correlations were used to model time to event.Results Thirty-one peer-reviewed publications reporting on 202 patients from 74 families with 59 different UMOD mutations were included. Median ages at onset of hyperuricemia, gout, and ESRD were 24, 40, and 56 years, respectively. Men developed gout and ESRD significantly earlier than did women (age at ESRD was 50 years for men and 60 for women; P=0.04, shared frailty model). Median ages at ESRD development were lowest with Cys77Tyr (37.5 years) and highest with Gln316Pro (65.5 years) UMOD mutations. Onset of ESRD was significantly earlier with UMOD mutations located within the epidermal growth factor domains 2 and 3 (range, 45-52 years; P,0.01 and 0.04, respectively) compared with the cysteine-rich domains (range, 60-65 years; by shared frailty model). ConclusionsThe UMOD genotype is related to the clinical phenotype of UAKD. This finding may assist in counseling of patients.

Serum uromodulin concentrations correlate with glomerular filtration rate in patients with chronic kidney disease

“…The relationship To date, most published studies exploring the association between uromodulin and kidney function concentrated on urinary uromodulin levels. 7,8,[25][26][27] The most recent study by Garimella et al 25 examined the predictive value of uromodulin excretion in urine to assess the progress of kidney disease and all -cause mortality in a large elderly population, including 2948 participants of the Framingham Heart Study. The higher levels of urinary uromodulin were associated with a reduced risk of progression of kidney disease and mortality.…”

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

“…While there are more than 100 inherited mutations in UMOD described (22)(23)(24)(25)(26)(27), most result in cysteine residue replacement, which disrupts disulfide bridging at critical nodes of protein folding. The majority of reported mutations reside within the portion of the gene that codes for the N-terminus.…”

A Novel <i>UMOD</i> Gene Mutation Associated with Uromodulin-associated Kidney Disease in a Young Woman with Moderate Kidney Dysfunction

“…MCKD type 2 and FJHN are considered forms of UAKD. However, UAKD is distinguished by its variable severity of symptoms, including hyperuricemia, gout and CKD (10,11). Meanwhile, MCKD type 2 is a rare type of progressive tubulointerstitial nephropathy with autosomal dominant inheritance that results in the development of ESRD in adulthood.…”

“…The uromodulin protein contains three epidermal growth factor (EGF) domains, a cysteine-rich region and a zona pellucida domain (10). The entire protein consists of 640 amino acids, including 48 cysteine residues (7.5%) required for the formation of disulfide bonds (12).…”

“…Similar to that observed in many previous cases, the UMOD gene mutation detected in our patient and her father was within exon 4 of the EGF domain 3, suggesting that the loss of a cysteine residue in the EGF domain leads to the initiation or progression of UAKD. In fact, the onset of ESRD occurs significantly earlier in individuals with UMOD mutations within EGF domain 2 or 3 (range, 45-52 years) compared to that associated with mutations within the cysteine-rich domains (range, 60-65 years) (10). The diagnosis of UAKD is mode based solely on the presence of UMOD mutations detected on a DNA analysis.…”