UMOD

Cilia effects upon perturbation of UMOD

Cilia number / % ciliated:

Decreased cilia number

Ciliogenesis screen results (3 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-3.84) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Mouse phenotype:

increased blood urea nitrogen level, decreased hemoglobin content, decreased hematocrit

Human ciliopathy phenotype:

ADTKD-UMOD: hyperuricaemia, gout, hypertension, urinary concentration defect, salt wasting, end-stage renal disease in 4th decade; small cortico-medullary cysts on renal ultrasound; tubular basement membrane disintegration, tubular atrophy, interstitial fibrosis. Phenotypic overlap with juvenile NPHP (nephronophthisis-MCKD complex). 46+ UMOD missense mutations reported.

Ciliopathy associations

• Autosomal Dominant Tubulointerstitial Kidney Disease

References: PMID:20172860

Subcellular localization

primary cilia, apical membrane, mitotic spindle pole

References: PMID:20172860, PMID:15029248

Functional category

• Ciliary assembly/disassembly
• Trafficking (BBSome, small GTPases, vesicular transport, ATPases)

Function

UMOD encodes uromodulin (Tamm-Horsfall protein), the most abundant urinary protein in humans, expressed at the apical surface of the thick ascending limb of Henle and early distal convoluted tubules. Heterozygous UMOD missense mutations cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD; OMIM #603860), encompassing medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricaemic nephropathy (FJHN, OMIM #162000), and glomerulocystic kidney disease (GCKD, OMIM #609886). Symptoms include hyperuricaemia, gout, hypertension, urinary concentration defect, salt wasting, and end-stage renal disease. Cilia mechanism: Zaucke et al. 2010 (Hum Mol Genet, PMID 20172860) demonstrated that UMOD is expressed in primary cilia of renal tubules in human kidney biopsies and colocalizes with nephrocystin-1 and kinesin family member 3A (KIF3A), with mitotic spindle pole localization confirmed. UMOD patient samples show significantly decreased ciliary UMOD expression compared with controls. Ciliary expression was confirmed by immunofluorescence and electron microscopy in cultured cells, placing UMOD within the renal cystoprotein family alongside polycystins, fibrocystin, and nephrocystins. MCKD2 is part of the "nephronophthisis-MCKD complex" with shared cystic histology.