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Uromodulin and kidney disease: a new entry for an old molecule

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Presentation on theme: "Uromodulin and kidney disease: a new entry for an old molecule"— Presentation transcript:

1 Uromodulin and kidney disease: a new entry for an old molecule
MCKD/FJHN Italian Consortium Gian Marco Ghiggeri Lyon ESPN 2008

2 Uromodulin Initially described by Tamm and Horsfall in 1950
Most abundant protein in human urine ( mg/day) Exclusively expressed in TAL and DCT Glomerulus proximal tubule Collecting duct distal tubule Henle’s loop descending limb ascending limb Dahan et al., J Am Soc Nephrol 2003

3 4 Non linear pH 9 150 kDa 5

4 Tamm Horsfall Glycoprotein
Igor TAMM and Frank L. Horsfall. Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc Soc Exp Biol Med May;74(1):106-8 J Exp Med Jan;95(1):71-97 J Exp Med Jan;95(1):99-104

5 Uromodulin structure ZP domain I II III D8C
Y Y Y Y Y Y Y I II III D8C ZP domain 22 31 281 334 585 640 614 ZP is a large domain, containing around 260 aa, including 8(10) conserved Cys residues, which are involved in disulphide bond formation. Found in a variety of receptor-like eukaryotic glycoproteins (mouse sperm receptors ZP1, ZP2, ZP3; alpha-tectorin) ZP domain proteins almost invariably contain single transmembrane domains or GPI anchors that are missing from the secreted mature proteins Responsible for the ability of ZP domain proteins to assemble into filaments Jovine et al.,Nat Cell Biol 2002

6 Uromodulin structure GPI anchor ZP domain I II III D8C
Y Y Y Y Y Y Y I II III D8C ZP domain 22 31 281 334 585 640 614 cf 568 EVYLCDIINEKCKPTCSGTRFRSGGIIDQSRVLNLGPITRKNVQAVVSRAASSSLGFLKVCLPLLLSATLTLMFQ 642 bt 569 EVYLCDTVNEKCRPTCPETRFRSGSIIDQTRVLNLGPITRKGGQAAMSRAAPSSLGLLQVWLPLLLSATLTLMSP 643 hs 567 EVYLCDTMNEKCKPTCSGTRFRSGSVIDQSRVLNLGPITRKGVQATVSRAFSS-LGLLKVWLPLLLSATLTLTFQ 640 mm 568 EVYLCDSTSEQCKPTCSGTRFRSGNFIDQTRVLNLGPITRQGVQASVSKAASSNLRLLSIWLLLFPSATLIFMVQ 642 rn 570 EVYLCDTMSEQCKPTCSGTRYRSGNFIDQTRVLNLGPITRQGVQASVSKAASSNLGFLSIWLLLFLSATLTLMVH 644 ****** .*:*:***. **:***..***:**********:. ** :*:* .* * :*.: * *: **** : GPI anchor Santambrogio et al.,Biochem Biophys Res Comm 2008

7 Uromodulin function Urothelial defence against infections
Urothelial defence against calcium oxalate crystals-induced damage Urothelial defence against ischemic damage Water / salt balance in TAL and DCT Mo et al, Am J Physiol Renal Physiol, 2003 Mo et al, Kidney Int, 2004 El-Achkar et al, JASN, 2008 Wiggins et al, Clin Chim Acta, 1987

8 Uromodulin Related Diseases

9

10 ALLELISM of MCKD, FJHN and GCKD
- Dominant tubulo-interstitial nephritis - Hypostenuria, ESRD, Medullary cysts - Hyperuricemia and gout FJHN - Phenotypic similarity with MCKD (no medullary cysts) - Tubulo Interstitial Nephropathy, GCKD - Glomerular cysts: dilatation of Bowman’s space - Sporadic or dominant disorder - Also part of metabolic syndrome (MODY5; HNF-1beta mut.)

11 Summary of UMOD published mutations
Aggiornare la lista mutazioni GPI 640 H177_R185del ZP domain 31 336 585 614 I II III IV 22 281 Y V93_G97del4ins D8C W202S C148Y C126R N128S G103C C135S C217R C248W C300G C150S C315R C317Y C148W C223Y T225L C255Y D59A R185S R204G R222P T225M C112R C170Y C217G C282R E188Vdel33 M229R C52W C195P P236L P236R C347G Q316P K307T C300Y C77Y Exon Exon 5 98% mutations (42/43) 43 mutations 26 Cys-affecting 1 Gly to Cys 13 other missense 3 in frame deletions

12 GCKD MCKD/FJHN

13 Normal MCKD

14 GCKD

15 MCKD/FJHN kidney biopsy
Dr. Vivette D’Agati, Dept of Pathology, Columbia Univ

16 Urinary uromodulin is reduced
in MCKD2/FJHN patients MCKD#1 1 2 1 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 Uromodulin urinary excretion in affected individuals: Amount of daily excreted uromodulin is 15 to 30 fold decreased (Bleyer et al., Kidney Int 2004) Excreted uromodulin is wild type only (Dahan et al., J Am Soc Nephrol, 2003)

17 MOLECULAR PATHOGENESIS
“In vitro” studies

18 WT C148W Unpermeabilized HEK293 after transfection (6 hrs)

19 Mutant uromodulin is retained in the ER
WT C150S

20 ANIMAL MODELS THP -/- Are more prone to develop
urinary tract infection. Do no develop MCKD Knock-in mice ? Raffi et al Kidney In, 2006

21 Mechanisms Urine concentration defect interaction with ROMK
Hyperuricemia idem TI fibrosis ? Cyst formation ?

22 Uromodulin Associated Kidney Diseases
UAKD Uromodulin Associated Kidney Diseases - Chr 17q12 (HNF1-beta) - Chr 1q21 ? - Chr 1q41 ?

23 Atypical familial juvenile hyperuricemic nephropathy associated with a HNF1B mutation
Bingham el al, Kidney Int 2003

24 Renal-specific inactivation of HNF1B
UMOD can be considered as direct transcriptional targets of HNF1B Gresh et al, EMBO J, 2004

25 UROMODULIN ASSOCIATED KIDNEY DISEASE
Control Umod Mutation ? Linkage 1q41 Hodanova et al Kidney Int 2005

26 CONCLUSIONS The re-discovery of an old actor
such as Uromodilun offers the opportunity to open a new area of research on renal fibrosis that may lead to important advancements

27 Thank You!

28 MCKD/FJHN Italian Consortium
G. Gaslini Institute, Genoa Gianluca Caridi Gian Marco Ghiggeri Clinical analysis Molecular analysis University of Turin Mario De Marchi Antonio Amoroso Molecular analysis University of Brescia Francesco Scolari Clinical analysis Kidney pathology DTI, Dibit-HSR, Milan Luca Rampoldi Cellular and animal models Linkage analysis University of Padua Luisa Murer Kidney pathology


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