Molecular Genetic Pathogenesis
Autosomal dominant tubulointerstitial kidney disease, UMOD-related (ADTKD-UMOD) is an endoplasmic reticulum storage disease resulting in chronic renal failure from deposition of abnormal uromodulin over time [Rampoldi et al 2003, Bleyer et al 2004].
Gene structure. The gene comprises 11 exons. Exon 1 is non-coding. Note: Exon numbering may vary in the literature; this GeneReview uses that of Williams et al [2009]. See Table A for a detailed summary of gene and protein information.
Pathogenic variants. More than 40 pathogenic variants have been found in families with ADTKD-UMOD [Hart et al 2002, Dahan et al 2003, Rampoldi et al 2003, Turner et al 2003, Wolf et al 2003, Kudo et al 2004, Lens et al 2005, Puig et al 2006]. Pathogenic variants are almost exclusively missense variants.
The majority of the pathogenic variants causing ADTKD-UMOD involve an addition or deletion of a cysteine residue or highly conserved polar residue that is likely to alter either disulfide bond formation, thereby disrupting the correct protein folding [Whiteman & Handford 2003], or hydrophobicity distribution responsible for protein spatial flexibility [Xu et al 1997].
Pathogenic variants have been identified in exons 3, 4, 5, and 7 of UMOD.
Table 4.
UMOD Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
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c.278_289delTCTGCCCCGAAGinsCCGCCTCCT | p.Val93_Gly97delinsAlaAlaSerCys | NM_003361.3 NP_003352.2 |
Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Uromodulin is a large glycoprotein with a large number of cysteine residues [Serafini-Cessi et al 2003] (reference sequence NP_001008390.1). Uromodulin is produced only in the thick ascending limb of Henle's loop of the renal tubule; therefore, disease is limited to the kidney. While uromodulin is the most common protein found in normal human urine, its function is uncertain. Uromodulin is likely responsible for maintaining the integrity of the thick ascending limb of Henle's loop, the kidney region in which the water permeability is remarkably low and salts are efficiently absorbed. Although it has been postulated that uromodulin is important in preventing urinary tract infections, individuals with abnormal uromodulin do not have an increased incidence of urinary tract infections or kidney stones.
Abnormal gene product. Increasing evidence suggests that intracellular accumulation of abnormal uromodulin leads to increased apoptosis and is likely an important contributor to the pathogenesis of this disorder [Williams et al 2009]. Abnormal uromodulin may also prevent the proper function of ion channels in the thick ascending limb, resulting in mild natriuresis leading to proximal tubular reabsorption of urate and hyperuricemia [Renigunta et al 2011].
Histochemical studies have shown abnormal uromodulin deposition in the endoplasmic reticulum of cells of the thick ascending limb of Henle's loop. In heterozygotes, urinary excretion of uromodulin is much less than half the expected amount, likely resulting from a dominant-negative effect (e.g., interference with synthesis of the normal uromodulin by abnormal uromodulin). Accordingly, the abnormal expression of the mutated uromodulin in the thick ascending limb of Henle's loop of the renal tubule decreases NaCl reabsorption and subsequently induces a state of volume contraction known to promote the proximal reabsorption of urate [Renigunta et al 2011].