Indian Journal of Nephrology About us |  Subscription |  e-Alerts  | Feedback | Login   
  Print this page Email this page   Small font sizeDefault font sizeIncrease font size
 Home | Current Issue | Archives| Ahead of print | Search |Instructions |  Editorial Board  

Users Online:1868

Official publication of the Indian Society of Nephrology
 ~  Similar in PUBMED
 ~  Search Pubmed for
 ~  Search in Google Scholar for
 ~Related articles
 ~  Article in PDF (842 KB)
 ~  Citation Manager
 ~  Access Statistics
 ~  Reader Comments
 ~  Email Alert *
 ~  Add to My List *
* Registration required (free)  

  Case Report
   Article Figures
   Article Tables

 Article Access Statistics
    PDF Downloaded124    
    Comments [Add]    
    Cited by others 2    

Recommend this journal


  Table of Contents  
Year : 2016  |  Volume : 26  |  Issue : 5  |  Page : 364-367

A novel heterozygous missense mutation in uromodulin gene in an Indian family with familial juvenile hyperuricemic nephropathy

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication29-Aug-2016

Correspondence Address:
S R Phadke
Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-4065.167277

Rights and Permissions


Familial juvenile hyperuricemic nephropathy (FJHN), characterized by early-onset hyperuricemia, reduced fractional excretion of uric acid, and chronic renal failure is caused due to mutation in uromodulin (UMOD) gene. We identified a novel mutation in a family with multiple members affected with FJHN. Ten coding exons of UMOD gene in three family members with clinical and biochemical features of FJHN and one unaffected family member were sequenced, and sequence variants were analyzed for the pathogenicity by bioinformatics studies. A heterozygous novel missense mutation (c. 949 T >G) in exon 5 leading to the replacement of cysteine by glycine at position 317 was identified in all three affected family members. This mutation has not been reported earlier in Human Gene Mutation Database, Human Genome Variation, Clinvar, and 1000 Genome. The mutation lies in the cysteine-rich 2 domain of the protein, and the affected residue is evolutionary conserved in other species. To our knowledge, this is the first report of the identification of UMOD mutation in an Indian family.

Keywords: Chronic renal failure, familial juvenile hyperuricemic nephropathy, gout, hyperuricemia, uromodulin

How to cite this article:
Saxena D, Srivastava P, Phadke S R. A novel heterozygous missense mutation in uromodulin gene in an Indian family with familial juvenile hyperuricemic nephropathy. Indian J Nephrol 2016;26:364-7

How to cite this URL:
Saxena D, Srivastava P, Phadke S R. A novel heterozygous missense mutation in uromodulin gene in an Indian family with familial juvenile hyperuricemic nephropathy. Indian J Nephrol [serial online] 2016 [cited 2022 Oct 3];26:364-7. Available from:

  Introduction Top

Familial juvenile hyperuricemic nephropathy (FJHN1; MIM 162000) is an autosomal dominant condition characterized by defective urinary concentrating ability, gouty arthritis, interstitial nephritis, and chronic renal failure. It is a genetically heterogeneous condition, caused due to mutation in three genes: Uromodulin (UMOD) (40%), renin (2.5%), and hepatocyte nuclear factor-1 beta (2.5%). Biochemical hallmarks of the disease are hyperuricemia out of proportion to the degree of renal failure and reduced fractional uric acid excretion. [1]

Here, we describe an Indian family with multiple members affected with FJHN1 due to a novel heterozygous missense mutation in exon 5 of UMOD gene.

  Case Report Top

A 17-year-old male presented with pain and swelling in small joints of hands, feet, knees, ankles, elbows, and wrists for 2 years along with the presence of nodules on the right little finger and the left ear lobe. On examination, swellings were present on second and third metacarpophalangeal joints and third proximal interphalangeal joints. There were tophi of size 2-3 cm with whitish discharge on the right little finger and of 0.5 cm on the left ear lobule [Figure 1]. His blood pressure was normal. The serum uric acid level was 13.9 mg/dl, and serum creatinine 1.4 mg/dl (normal uric acid level in >18 years old: 6.2 ± 0.8 mg/dl). [2] The fractional excretion of uric acid was reduced (2.93%). Ultrasonography showed normal-sized kidneys with normal echogenicity. There were multiple family members affected with the same disorder; some had only gouty arthropathy and others had both gouty arthropathy and renal disease [Table 1] and [Table 2]. His father had died at the age of 42 years due to chronic kidney disease and had gouty arthritis. One of his elder brothers and one paternal uncle's son has gout along with kidney disease, and one brother has only gouty arthritis [Figure 2].
Figure 1: Proband showing a nodule on left ear lobe and another on right little finger with whitish discharge

Click here to view
Figure 2: Family pedigree showing multiple affected members

Click here to view
Table 1: Clinical features of proband and his family members

Click here to view
Table 2: Investigations of the proband and his brother

Click here to view

Informed consent was obtained from the three affected individuals for deoxyribonucleic acid analysis, collection of clinical data, and publication of photographs. The 10 coding exons of UMOD gene were amplified by polymerase chain reaction and cycle sequenced by capillary electrophoresis using an ABI 310 sequencer (Applied Biosystems Foster City, CA, USA). The pathogenicity of the variant found was analyzed using various bioinformatics tools.

A heterozygous missense variant (c. 949 T >G) in exon 5 [Figure 3] was identified in the proband and two affected brothers causing substitution of cysteine by glycine at codon position 317 (p.C317G). This particular amino acid change was not present in the unaffected sister. It is a novel variant, not reported in 1000 genomes, Clinvar, Human Genome Mutation Database, and Human Genome Variation. The affected residue locates within the cysteine-rich 2 domain and is immediately preceded by a highly conserved cysteine residue. Various bioinformatics tools such as mutation taster, PolyPhen and Sorting Intolerant from Tolerant also predicted it to be pathogenic. This amino acid residue is conserved across other animal species. Based on the above evidence, we concluded that this novel variant is very likely the causal pathogenic mutation.
Figure 3: Proband showing heterozygous mutation c.949 T>G in exon 5 of uromodulin gene causing substitution of cysteine by glycine at position 317

Click here to view

  Discussion Top

UMOD also called as Tamm-Horsfall protein is a polymeric protein located on the tubular cells lining the thick ascending limb of the loop of Henle and early distal convoluted tubules. From the apical membrane, it is secreted into the tubular lumen where it polymerizes into a water impermeable gel-like structure that modulates salt transport, urine concentration, and urate metabolism. [3] UMOD prevents interstitial cystitis, urinary tract infections, and formation of urinary stones. [4] Common genetic variants in UMOD gene have been found to be associated with hypertension, reduced renal function, and increased risk of chronic renal failure. [5],[6] UMOD is the most common of the three genes known to cause FJHN. Other disorders caused by mutation in UMOD are medullary cystic kidney disease type 2 (MIM 603860) and glomerulocystic kidney disease (MIM 609886). [7]

Until date, more than 70 mutations have been described in UMOD and most of them are clustered in exon 4 (83.8%), 5 (8%), and 8 (8%) of UMOD gene. Two-thirds of these mutations cause substitution of cysteine residues or highly conserved polar amino acids. In the present family, the mutation c. 949 T >G replaces cysteine with glycine at position 317. Substitution of cysteine residue can alter the disulfide bond formation that interferes with correct folding of the UMOD protein. The misfolded protein accumulates in the endoplasmic reticulum of tubular cells that elicits an adaptive response called as "unfolded protein response" causing cell death. [8] Rampoldi et al. have shown that substitution of cysteine by tyrosine (Cys317Tyr) at the same position leads to delay in export of UMOD to plasma membrane due to longer retention time in endoplasmic reticulum. [7] The co-segregation of the mutation in affected sibs supports the pathogenic nature. There is marked interfamilial and intrafamilial variability that was also seen in the present family. Hyperuricemia is present in 83.3% of the cases and gout in 45% of mutation - positive cases. Median age of onset of end-stage renal disease (ESRD) was earlier in cases with mutation in epidermal growth factor (EGF)-2 and EGF3 domains and later in cases with mutation in domain of 8 cysteine (D8C) and cysteine - rich regions 1 and 2. However, there is no correlation between the presence of hyperuricemia or gout and development of ESRD. [9]

Definitive treatment is renal transplantation. Use of uricosuric drugs such as allopurinol has a definite role in decreasing hyperuricemia and features related to gout. However, the efficacy of these medications in slowing the progression of renal disease is still not clear. [10] Mutation detection helps in confirmation of the diagnosis of this rare and underdiagnosed condition. This is the first report of a case of FJHN from Indian population. Mutation analysis can be used for presymptomatic diagnosis of relatives. This is especially of importance when the relatives are screened as kidney donors.


We would like to thank Indian Council of Medical Research for their support.

Financial support and sponsorship

Supported by ICMR.

Conflicts of interest

There are no conflicts of interest.

  References Top

Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig JG, et al. Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003;88:1398-401.  Back to cited text no. 1
Wilcox WD. Abnormal serum uric acid levels in children. J Pediatr 1996;128:731-41.  Back to cited text no. 2
Muchmore AV, Decker JM. Uromodulin: A unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. Science 1985;229:479-81.  Back to cited text no. 3
Leeker A, Kreft B, Sandmann J, Bates J, Wasenauer G, Múller H, et al. Tamm-Horsfall protein inhibits binding of S- and P-fimbriated Escherichia coli to human renal tubular epithelial cells. Exp Nephrol 1997;5:38-46.  Back to cited text no. 4
Graham LA, Padmanabhan S, Fraser NJ, Kumar S, Bates JM, Raffi HS, et al. Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension 2014;63:551-8.  Back to cited text no. 5
Prajczer S, Heidenreich U, Pfaller W, Kotanko P, Lhotta K, Jennings P. Evidence for a role of uromodulin in chronic kidney disease progression. Nephrol Dial Transplant 2010;25:1896-903.  Back to cited text no. 6
Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, et al. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 2003;12:3369-84.  Back to cited text no. 7
Adam J, Bollée G, Fougeray S, Noël LH, Antignac C, Knebelman B, et al. Endoplasmic reticulum stress in UMOD-related kidney disease: A human pathologic study. Am J Kidney Dis 2012;59:117-21.  Back to cited text no. 8
Moskowitz JL, Piret SE, Lhotta K, Kitzler TM, Tashman AP, Velez E, et al. Association between genotype and phenotype in uromodulin-associated kidney disease. Clin J Am Soc Nephrol 2013;8:1349-57.  Back to cited text no. 9
Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van'T Hoff W, et al. Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM 2002;95:597-607.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]

This article has been cited by
1 A novel likely pathogenic variant in the UMOD gene in a family with autosomal dominant tubulointerstitial kidney disease: a case report
Ying Wang, Haibo Liu, Qingnan He, Zhuwen Yi, Yongzhen Li, Xiqiang Dang
BMC Nephrology. 2020; 21(1)
[Pubmed] | [DOI]
2 Prevalence of inherited changes of uric acid levels in kidney dysfunction including stage 5 D and T: a systematic review
Fateme Shamekhi Amiri, Zohreh Rostami
Renal Replacement Therapy. 2020; 6(1)
[Pubmed] | [DOI]


Print this article  Email this article


Indian Journal of Nephrology
Published by Wolters Kluwer - Medknow
Online since 20th Sept '07