Uromodulin

UMOD
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4WRN
Identifiers
Aliases	UMOD, ADMCKD2, FJHN, HNFJ, HNFJ1, MCKD2, THGP, THP, uromodulin, ADTKD1
External IDs	OMIM: 191845 MGI: 102674 HomoloGene: 2522 GeneCards: UMOD
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p12.3 Start 20,333,051 bp[1] End 20,356,301 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 F2|7 63.88 cM Start 119,061,934 bp[2] End 119,078,505 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in renal medulla kidney kidney tubule metanephric glomerulus body of pancreas urethra gallbladder bone marrow cells body of stomach fundus Top expressed in kidney distal tubule Ascending limb of loop of Henle thick ascending limb of loop of Henle thin ascending limb of loop of Henle distal convoluted tubule proximal tubule superior frontal gyrus sexually immature organism cortical collecting duct More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding IgG binding Cellular component cell projection spindle pole membrane plasma membrane extracellular region basolateral plasma membrane apical plasma membrane ciliary membrane anchored component of membrane extracellular exosome extrinsic component of membrane Golgi lumen cilium Biological process leukocyte cell-cell adhesion chemical homeostasis heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules excretion metanephric distal convoluted tubule development metanephric ascending thin limb development cellular defense response neutrophil migration metanephric thick ascending limb development negative regulation of cell population proliferation protein N-linked glycosylation via asparagine ion homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7369 22242 Ensembl ENSG00000169344 ENSMUSG00000030963 UniProt P07911 Q91X17 RefSeq (mRNA) NM_001008389 NM_001278614 NM_003361 NM_001378232 NM_001378233 NM_001378234 NM_001378235 NM_001378237 NM_001278605 NM_009470 RefSeq (protein) NP_001008390 NP_001265543 NP_003352 NP_001365161 NP_001365162 NP_001365163 NP_001365164 NP_001365166 NP_001265534 NP_033496 Location (UCSC) Chr 16: 20.33 – 20.36 Mb Chr 7: 119.06 – 119.08 Mb PubMed search [3] [4]
Wikidata
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Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a zona pellucida-like domain-containing glycoprotein that in humans is encoded by the UMOD gene.^[5][6] Uromodulin is the most abundant protein excreted in ordinary urine.^[7]

Gene

The human UMOD gene is located on chromosome 16. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.^[6]

Protein

THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da.^[7] When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most abundant protein in normal human urine (results based on MSMS determinations).^[8] It is the matrix of urinary casts derived from the secretion of renal tubular cells.

Structure

Uromodulin consists of an EGF domain (EGF I); two calcium-binding EGF domains (EGF II, III); a cysteine-rich decoy module consisting of a β-hairpin and a D10C domain (previously referred to as D8C); a fourth EGF domain; and a C-terminal bipartite Zona pellucida-like (ZP) module consisting of ZP-N and ZP-C domains separated by an interdomain linker.^[9][10] The ZP domain polymerizes into filaments,^[11] with protruding arms that correspond to the EGF I-III domains and the decoy module.^{[10][12][13][14]}

Function

Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria.^[6]

The function of THP is not well understood. Studies using THP deficient mice revealed that THP may have a role in regulatory physiology and actually participates in transporter function.^[15] A role in bacterial binding and sequestration is suggested by studies showing that Escherichia coli which express MS (mannose-sensitive) pili or fimbriae (also fimbria, from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.^[7] THP may also be important in protection from kidney injury by down-regulating inflammation.^[16]

Clinical significance

Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing kidney stones or calculus. Tamm–Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable. However, decreased levels of Tamm–Horsfall in urine have been found to be a good indicator of kidney stones.^[7]

Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and autosomal dominant tubulointerstitial kidney disease (ADTKD) (previously familial juvenile hyperuricemic nephropathy (FJHN)). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive kidney failure.^[6]

Antibodies to Tamm–Horsfall protein have been seen in various forms of nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.^[17]

Another disease associated with mutations in this gene is Uromodulin-associated Kidney Disease (UKD), a rare autosomal dominant progressive failure of the kidneys.

In multiple myeloma, there is often protein cast in the distal convoluted tubule and collecting duct of the kidneys, mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also containing Tamm–Horsfall protein.^[18][19] This is known as myeloma cast nephropathy.

History

The glycoprotein was first purified in 1950 by Igor Tamm and Frank Horsfall from the urine of healthy individuals.^[20] It was later detected in the urine of all mammals studied.

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
• OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
• Tamm–Horsfall protein deposition

This page was last edited on 13 January 2024, at 21:29