GeneBe

UMOD

protein-coding

uromodulin

Gene summary

The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_003361.4

Inheritance

AD

ClinVar variants

P:122U:293B:115

Top phenotype

Tubulointerstitial kidney disease, autosomal dominant, 1; Glomerulocystic kidney disease with hyperuricemia and isosthenuria

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr16:20,333,051-20,356,301

External References & Databases

Ensembl (ENSG00000169344)NCBI Gene (7369)OMIM (191845)HGNC:12559GenCCUniProt (P07911)AlphaFoldClinVar (UMOD)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glomerulocystic kidney disease with hyperuricemia and isosthenuriaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012356

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal dominant medullary cystic kidney disease with or without hyperuricemiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008264

Submitter: ClinGen

*UMOD* was first reported in relation to autosomal dominant tubulointerstitial kidney disease (ADTKD) in 2002 (Hart et al., PMID 12471200). ADTKD due to *UMOD* pathogenic variants (ADTKD-*UMOD*) is diagnosed in individuals with a family history of chronic kidney disease leading to end stage kidney disease (ESKD), with little to no protein or blood in the urine. Hyperuricemia and gout may also be associated with family history. ADTKD-*UMOD* has been reported in the literature under the names familial juvenile hyperuricemic nephropathy type 1 and medullary cystic kidney disease type 2 (PMID 25738250). At least 125 unique variants (including missense, in-frame indel, and in-frame deletions) have been reported in humans with 97% of pathogenic variants clustering in exons 3 and 4 (PMID 32450155, PMID 32954071). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of Case Level Data: Variants in this gene have been reported in at least 19 individuals (PMID 12471200, PMID 12629136, PMID 12900848, PMID 1451790, PMID 14570709 PMID 32954071). Variants in this gene segregated with disease in 83 additional family members. The mechanism for disease is heterozygous toxic gain of function (PMID 14570709, PMID 16883323, PMID 28990932) with experimental evidence suggesting mutant UMOD is retained in the endoplasmic reticulum, the stress inducing the unfolded protein response (UPR), leading to tubular cell atrophy. Summary of Experimental Evidence: This gene-disease association is supported by expression studies in patient kidney biopsies, urine and serum, in vitro functional alteration studies, and mouse models (PMID 14570709, PMID 16883323, PMID 27729211, PMID 28990932, PMID 32926855, PMID 32954071). In summary, *UMOD* is definitively associated with autosomal dominant tubulointerstitial kidney disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP Working Group on 01/13/2021 (SOP Version 8).

autosomal dominant medullary cystic kidney disease with hyperuricemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019511

Submitter: Orphanet

familial juvenile hyperuricemic nephropathy type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008073

Submitter: PanelApp Australia

familial juvenile hyperuricemic nephropathy type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008073

Submitter: Labcorp Genetics (formerly Invitae)

familial juvenile hyperuricemic nephropathy type 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008073

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Tubulointerstitial kidney disease, autosomal dominant, 1; Glomerulocystic kidney disease with hyperuricemia and isosthenuriaAD

Manifestation: Renal

Intervention: Renal

Rationale: In Glomerulocystic kidney disease with hyperuricemia and isosthenuria and Tubulointerstitial kidney disease, autosomal dominant, medical treatment may be beneficial (eg, allopurinol related to gout and preservation of renal function)

Comments: In some forms of MCKD2, it appears that isolated cysts can occur without hyperuricemia

Refs: 7396593; 1975911; 1873940; 9266353; 9686952; 10780922; 12205338; 12471200; 14570709; 12634862; 12629136; 16883323Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UMOD variants in ClinVar

13 Conditions Cataloged
not providedTotal: 325
Familial juvenile hyperuricemic nephropathy type 1Total: 298
Inborn genetic diseasesTotal: 95
UMOD-related disorderTotal: 45
not specifiedTotal: 14
Autosomal dominant medullary cystic kidney disease with or without hyperuricemiaTotal: 11
Kidney disorderTotal: 9
Kidney failureTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003361.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
72
clinvar
4
clinvar
 81
missense
31
clinvar
89
clinvar
256
clinvar
35
clinvar
2
clinvar
 413
nonsense
1
clinvar
1
clinvar
17
clinvar
1
clinvar
 20
start loss
0
frameshift
10
clinvar
1
clinvar
 11
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total32902931096530

Highest pathogenic variant AF is 0.000010802581

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 79 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003361.4RefSeqNP_003352.210MANE Select
ENST00000396138.9EnsemblENSP00000379442.510MANE Select
NM_001008389.3RefSeqNP_001008390.110Standard
NM_001278614.2RefSeqNP_001265543.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Post-translational protein modification
  • Metabolism of proteins
  • Asparagine N-linked glycosylation

Biological Process

  • cellular defense response
  • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
  • leukocyte cell-cell adhesion
  • excretion
  • negative regulation of cell population proliferation

Molecular Function

  • calcium ion binding
  • IgG binding

Cellular Component

  • spindle pole
  • Golgi lumen
  • cilium
  • basolateral plasma membrane
  • apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000570689
Coding exons
10
Length
23250
Individuals with no LoFs
125655
Homozygous LoFs
0
Heterozygous LoFs
93
Defined
125748
p
0.000370
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9983363920.8580.00002434146
Missense (PolyPhen)94148.410.633391657
Synonymous-0.2341801761.020.00001301251
Loss of Function0.4622729.70.9090.00000154301

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000800.00080rare
Latino/Admixed American0.000440.00043rare
Ashkenazi Jewish00.0absent
East Asian0.00210.0015notable
Finnish00.0absent
European (Non-Finnish)0.000270.00027rare
South Asian0.000130.00013rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Uromodulin: Functions in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop (TALH), where it promotes formation of complex filamentous gel-like structure that may play a role in the water barrier permeability (Probable). May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF (PubMed:3498215). Facilitates neutrophil migration across renal epithelia (PubMed:20798515). {ECO:0000269|PubMed:20798515, ECO:0000269|PubMed:3498215, ECO:0000305}.;
Disease
DISEASE: Familial juvenile hyperuricemic nephropathy 1 (HNFJ1) [MIM:162000]: A renal disease characterized by juvenile onset of hyperuricemia, polyuria, progressive renal failure, and gout. The disease is associated with interstitial pathological changes resulting in fibrosis. {ECO:0000269|PubMed:12471200, ECO:0000269|PubMed:12629136, ECO:0000269|PubMed:12900848, ECO:0000269|PubMed:14569098, ECO:0000269|PubMed:14570709, ECO:0000269|PubMed:15086896, ECO:0000269|PubMed:15575003, ECO:0000269|PubMed:15983957, ECO:0000269|PubMed:17010121, ECO:0000269|PubMed:21060763, ECO:0000269|PubMed:22776760, ECO:0000269|PubMed:23197950, ECO:0000269|PubMed:23988501, ECO:0000269|PubMed:25436415}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Medullary cystic kidney disease 2 (MCKD2) [MIM:603860]: A form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in end-stage renal failure by the sixth decade. {ECO:0000269|PubMed:12471200, ECO:0000269|PubMed:14531790, ECO:0000269|PubMed:14570709, ECO:0000269|PubMed:17010121, ECO:0000269|PubMed:25436415, ECO:0000269|PubMed:27729211}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI) [MIM:609886]: A renal disorder characterized by a cystic dilation of Bowman space, a collapse of glomerular tuft, and hyperuricemia due to low fractional excretion of uric acid and severe impairment of urine concentrating ability. {ECO:0000269|PubMed:14570709, ECO:0000269|PubMed:17010121}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.245

Intolerance Scores

LoFtool
0.110
RVIS EVS
-0.55
RVIS percentile EVS
19.8

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.667

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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