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A Mutation in the TRPC6 Cation Channel Causes Familial Focal Segmental Glomerulosclerosis
Michelle P. Winn,1,2*Peter J. Conlon,4Kelvin L. Lynn,5Merry Kay Farrington,1,2Tony Creazzo,3April F. Hawkins,1Nikki Daskalakis,1,2Shu Ying Kwan,2Seth Ebersviller,2James L. Burchette,5Margaret A. Pericak-Vance,1,2David N. Howell,5Jeffery M. Vance,1,2*Paul B. Rosenberg1*
Focal and segmental glomerulosclerosis (FSGS) is a kidney disorderof unknown etiology, and up to 20% of patients on dialysis havebeen diagnosed with it. Here we show that a large family withhereditary FSGS carries a missense mutation in the TRPC6 geneon chromosome 11q, encoding the ion-channel protein transientreceptor potential cation channel 6 (TRPC6). The proline-to-glutaminesubstitution at position 112, which occurs in a highly conservedregion of the protein, enhances TRPC6-mediated calcium signalsin response to agonists such as angiotensin II and appears toalter the intracellular distribution of TRPC6 protein. Previouswork has emphasized the importance of cytoskeletal and structuralproteins in proteinuric kidney diseases. Our findings suggestan alternative mechanism for the pathogenesis of glomerulardisease.
1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. 2 Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. 3 Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. 4 Department of Nephrology, Beaumont Hospital, Dublin, Ireland. 5 Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand. 5Department of Pathology, Duke University Medical Center and Durham VA Medical Center, Durham, NC 27710, USA.
* To whom correspondence should be addressed. E-mail: michelle.winn{at}duke.edu (M.P.W.); jeff{at}chg.duhs.duke.edu (J.M.V.); rosen029{at}mc.duke.edu (P.B.R.)
R. Puertollano and K. Kiselyov (2009)
Am J Physiol Renal Physiol
296, F1245-F1254
|Abstract »|Full Text »|PDF »
TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis.
S. Santin, E. Ars, S. Rossetti, E. Salido, I. Silva, R. Garcia-Maset, I. Gimenez, P. Ruiz, S. Mendizabal, J. L. Nieto, et al. (2009)
Nephrol. Dial. Transplant.
|Abstract »|Full Text »|PDF »
Sensitizing the Slit Diaphragm with TRPC6 Ion Channels.
C. C. Moller, J. Flesche, and J. Reiser (2009)
J. Am. Soc. Nephrol.
20, 950-953
|Abstract »|Full Text »|PDF »
Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.
A. Pierides, K. Voskarides, Y. Athanasiou, K. Ioannou, L. Damianou, M. Arsali, M. Zavros, M. Pierides, V. Vargemezis, C. Patsias, et al. (2009)
Nephrol. Dial. Transplant.
|Abstract »|Full Text »|PDF »
Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound.
S. Kiyonaka, K. Kato, M. Nishida, K. Mio, T. Numaga, Y. Sawaguchi, T. Yoshida, M. Wakamori, E. Mori, T. Numata, et al. (2009)
PNAS
106, 5400-5405
|Abstract »|Full Text »|PDF »
Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-{gamma}1.
Y. Harita, H. Kurihara, H. Kosako, T. Tezuka, T. Sekine, T. Igarashi, I. Ohsawa, S. Ohta, and S. Hattori (2009)
J. Biol. Chem.
284, 8951-8962
|Abstract »|Full Text »|PDF »
Canonical Transient Receptor Potential Channel (TRPC) 3 and TRPC6 Associate with Large-Conductance Ca2+-Activated K+ (BKCa) Channels: Role in BKCa Trafficking to the Surface of Cultured Podocytes.
E. Y. Kim, C. P. Alvarez-Baron, and S. E. Dryer (2009)
Mol. Pharmacol.
75, 466-477
|Abstract »|Full Text »|PDF »
Lipid-Protein Interactions along the Slit Diaphragm of Podocytes.
TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription.
J. Schlondorff, D. del Camino, R. Carrasquillo, V. Lacey, and M. R. Pollak (2009)
Am J Physiol Cell Physiol
296, C558-C569
|Abstract »|Full Text »|PDF »
Physiology and pathophysiology of canonical transient receptor potential channels.
Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation.
M. Muller, K. Essin, K. Hill, H. Beschmann, S. Rubant, C. M. Schempp, M. Gollasch, W. H. Boehncke, C. Harteneck, W. E. Muller, et al. (2008)
J. Biol. Chem.
283, 33942-33954
|Abstract »|Full Text »|PDF »
TRP_2, a Lipid/Trafficking Domain That Mediates Diacylglycerol-induced Vesicle Fusion.
D. B. van Rossum, D. Oberdick, Y. Rbaibi, G. Bhardwaj, R. K. Barrow, N. Nikolaidis, S. H. Snyder, K. Kiselyov, and R. L. Patterson (2008)
J. Biol. Chem.
283, 34384-34392
|Abstract »|Full Text »|PDF »
Altered functional properties of a TRPM2 variant in Guamanian ALS and PD.
M. C. Hermosura, A. M. Cui, R. C. V. Go, B. Davenport, C. M. Shetler, J. W. Heizer, C. Schmitz, G. Mocz, R. M. Garruto, and A.-L. Perraud (2008)
PNAS
105, 18029-18034
|Abstract »|Full Text »|PDF »
Hemopexin Induces Nephrin-Dependent Reorganization of the Actin Cytoskeleton in Podocytes.
R. Lennon, A. Singh, G. I. Welsh, R. J. Coward, S. Satchell, L. Ni, P. W. Mathieson, W. W. Bakker, and M. A. Saleem (2008)
J. Am. Soc. Nephrol.
19, 2140-2149
|Abstract »|Full Text »|PDF »
Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.
M. Lowik, E. Levtchenko, D. Westra, P. Groenen, E. Steenbergen, J. Weening, M. Lilien, L. Monnens, and L. v. d. Heuvel (2008)
Nephrol. Dial. Transplant.
23, 3146-3151
|Abstract »|Full Text »|PDF »
The molecular and functional phenotype of glomerular podocytes reveals key features of contractile smooth muscle cells.
M. A. Saleem, J. Zavadil, M. Bailly, K. McGee, I. R. Witherden, H. Pavenstadt, H. Hsu, J. Sanday, S. C. Satchell, R. Lennon, et al. (2008)
Am J Physiol Renal Physiol
295, F959-F970
|Abstract »|Full Text »|PDF »
Nephrin binds to the COOH terminus of a large-conductance Ca2+-activated K+ channel isoform and regulates its expression on the cell surface.
E. Y. Kim, K.-J. Choi, and S. E. Dryer (2008)
Am J Physiol Renal Physiol
295, F235-F246
|Abstract »|Full Text »|PDF »
2007 Young Investigator Award: TRP'ing into a New Era for Glomerular Disease.
Mice Lacking Homer 1 Exhibit a Skeletal Myopathy Characterized by Abnormal Transient Receptor Potential Channel Activity.
J. A. Stiber, Z.-S. Zhang, J. Burch, J. P. Eu, S. Zhang, G. A. Truskey, M. Seth, N. Yamaguchi, G. Meissner, R. Shah, et al. (2008)
Mol. Cell. Biol.
28, 2637-2647
|Abstract »|Full Text »|PDF »
Neph1, a Component of the Kidney Slit Diaphragm, Is Tyrosine-phosphorylated by the Src Family Tyrosine Kinase and Modulates Intracellular Signaling by Binding to Grb2.
Y. Harita, H. Kurihara, H. Kosako, T. Tezuka, T. Sekine, T. Igarashi, and S. Hattori (2008)
J. Biol. Chem.
283, 9177-9186
|Abstract »|Full Text »|PDF »
Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease.
R. M. Salem, P. E. Cadman, Y. Chen, F. Rao, G. Wen, B. A. Hamilton, B. K. Rana, D. W. Smith, M. Stridsberg, H. J. Ward, et al. (2008)
J. Am. Soc. Nephrol.
19, 600-614
|Abstract »|Full Text »|PDF »
Development of the renal glomerulus: good neighbors and good fences.
Specific Podocin Mutations Correlate with Age of Onset in Steroid-Resistant Nephrotic Syndrome.
B. Hinkes, C. Vlangos, S. Heeringa, B. Mucha, R. Gbadegesin, J. Liu, K. Hasselbacher, F. Ozaltin, F. Hildebrandt, and and Members of the APN Study Group (2008)
J. Am. Soc. Nephrol.
19, 365-371
|Abstract »|Full Text »|PDF »
Identification of BRAF as a new interactor of PLC{varepsilon}1, the protein mutated in nephrotic syndrome type 3.
H. Chaib, B. E. Hoskins, S. Ashraf, M. Goyal, R. C. Wiggins, and F. Hildebrandt (2008)
Am J Physiol Renal Physiol
294, F93-F99
|Abstract »|Full Text »|PDF »
A Case of Familial Kidney Disease.
M. R. Pollak, M. P. Alexander, and J. M. Henderson (2007)
Clin. J. Am. Soc. Nephrol.
2, 1367-1374
|Full Text »|PDF »
COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy.
K. Voskarides, L. Damianou, V. Neocleous, I. Zouvani, S. Christodoulidou, V. Hadjiconstantinou, K. Ioannou, Y. Athanasiou, C. Patsias, E. Alexopoulos, et al. (2007)
J. Am. Soc. Nephrol.
18, 3004-3016
|Abstract »|Full Text »|PDF »
Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes.
S. Graham, M. Ding, S. Sours-Brothers, T. Yorio, J.-X. Ma, and R. Ma (2007)
Am J Physiol Renal Physiol
293, F1381-F1390
|Abstract »|Full Text »|PDF »
Molecular architecture of the glomerular slit diaphragm: lessons learnt for a better understanding of disease pathogenesis.
H. Holthofer (2007)
Nephrol. Dial. Transplant.
22, 2124-2128
|Full Text »|PDF »
Familial nephrotic syndrome: PLCE1 enters the fray.
J. A. Jefferson and S. J. Shankland (2007)
Nephrol. Dial. Transplant.
22, 1849-1852
|Full Text »|PDF »
Genetic Susceptibility, HIV Infection, and the Kidney.
K. Kiryluk, J. Martino, and A. G. Gharavi (2007)
Clin. J. Am. Soc. Nephrol.
2, S25-S35
|Abstract »|Full Text »|PDF »
Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes.
K. Asanuma, K. N. Campbell, K. Kim, C. Faul, and P. Mundel (2007)
PNAS
104, 10134-10139
|Abstract »|Full Text »|PDF »
A Proposed Taxonomy for the Podocytopathies: A Reassessment of the Primary Nephrotic Diseases.
L. Barisoni, H. W. Schnaper, and J. B. Kopp (2007)
Clin. J. Am. Soc. Nephrol.
2, 529-542
|Abstract »|Full Text »|PDF »
Nephrin Is Critical for the Action of Insulin on Human Glomerular Podocytes.
R. J.M. Coward, G. I. Welsh, A. Koziell, S. Hussain, R. Lennon, L. Ni, J. M. Tavare, P. W. Mathieson, and M. A. Saleem (2007)
Diabetes
56, 1127-1135
|Abstract »|Full Text »|PDF »
Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases Are Caused by Mutations in 4 Genes (NPHS1, NPHS2, WT1, and LAMB2).
B. G. Hinkes, B. Mucha, C. N. Vlangos, R. Gbadegesin, J. Liu, K. Hasselbacher, D. Hangan, F. Ozaltin, M. Zenker, F. Hildebrandt, et al. (2007)
Pediatrics
119, e907-e919
|Abstract »|Full Text »|PDF »
G{alpha}q-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin.
I. Singh, N. Knezevic, G. U. Ahmmed, V. Kini, A. B. Malik, and D. Mehta (2007)
J. Biol. Chem.
282, 7833-7843
|Abstract »|Full Text »|PDF »
Characterization of a large Lebanese family segregating IgA nephropathy.
H. H. Karnib, S. Sanna-Cherchi, P. A. Zalloua, W. Medawar, V. D. D'Agati, R. P. Lifton, K. Badr, and A. G. Gharavi (2007)
Nephrol. Dial. Transplant.
22, 772-777
|Abstract »|Full Text »|PDF »
{alpha}-Actinin-4 Is Required for Normal Podocyte Adhesion.
S. V. Dandapani, H. Sugimoto, B. D. Matthews, R. J. Kolb, S. Sinha, R. E. Gerszten, J. Zhou, D. E. Ingber, R. Kalluri, and M. R. Pollak (2007)
J. Biol. Chem.
282, 467-477
|Abstract »|Full Text »|PDF »
Dynamics at the slit diaphragm--is nephrin actin'?.
M. J. Moeller (2007)
Nephrol. Dial. Transplant.
22, 37-39
|Full Text »|PDF »
Transient Receptor Potential Cation Channels in Disease.
B. Nilius, G. Owsianik, T. Voets, and J. A. Peters (2007)
Physiol Rev
87, 165-217
|Abstract »|Full Text »|PDF »
Recessive NPHS2 (Podocin) Mutations Are Rare in Adult-Onset Idiopathic Focal Segmental Glomerulosclerosis.
N. He, A. Zahirieh, Y. Mei, B. Lee, S. Senthilnathan, B. Wong, B. Mucha, F. Hildebrandt, D. E. Cole, D. Cattran, et al. (2007)
Clin. J. Am. Soc. Nephrol.
2, 31-37
|Abstract »|Full Text »|PDF »
Induction of TRPC6 Channel in Acquired Forms of Proteinuric Kidney Disease.
C. C. Moller, C. Wei, M. M. Altintas, J. Li, A. Greka, T. Ohse, J. W. Pippin, M. P. Rastaldi, S. Wawersik, S. Schiavi, et al. (2007)
J. Am. Soc. Nephrol.
18, 29-36
|Abstract »|Full Text »|PDF »
Inaugural Article: Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels.
T. B. Huber, B. Schermer, R. U. Muller, M. Hohne, M. Bartram, A. Calixto, H. Hagmann, C. Reinhardt, F. Koos, K. Kunzelmann, et al. (2006)
PNAS
103, 17079-17086
|Abstract »|Full Text »|PDF »
Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome.
A. Kitamura, H. Tsukaguchi, K. Iijima, J. Araki, M. Hattori, M. Ikeda, M. Honda, K. Nozu, H. Nakazato, N. Yoshikawa, et al. (2006)
Nephrol. Dial. Transplant.
21, 3133-3138
|Full Text »|PDF »
A common mechanism underlies stretch activation and receptor activation of TRPC6 channels.
M. A. Spassova, T. Hewavitharana, W. Xu, J. Soboloff, and D. L. Gill (2006)
PNAS
103, 16586-16591
|Abstract »|Full Text »|PDF »
An Ancestral Haplotype Defines Susceptibility to Doxorubicin Nephropathy in the Laboratory Mouse.
Z. Zheng, P. Pavlidis, S. Chua, V. D. D'Agati, and A. G. Gharavi (2006)
J. Am. Soc. Nephrol.
17, 1796-1800
|Abstract »|Full Text »|PDF »
Identification and localization of TRPC channels in the rat kidney.
M. Goel, W. G. Sinkins, C.-D. Zuo, M. Estacion, and W. P. Schilling (2006)
Am J Physiol Renal Physiol
290, F1241-F1252
|Abstract »|Full Text »|PDF »
Hereditary proteinuria syndromes and mechanisms of proteinuria..
K. Tryggvason, J. Patrakka, and J. Wartiovaara (2006)
N. Engl. J. Med.
354, 1387-1401
|Full Text »|PDF »
Store-Operated Ca2+ Channel in Renal Microcirculation and Glomeruli.
R. Ma, J. Du, S. Sours, and M. Ding (2006)
Experimental Biology and Medicine
231, 145-153
|Abstract »|Full Text »|PDF »
Genetic factors in progressive renal disease: the good ones, the bad ones and the ugly ducklings.
M. Eikmans, J. A. Aben, K. Koop, H. J. Baelde, E. de Heer, and J. A. Bruijn (2006)
Nephrol. Dial. Transplant.
21, 257-260
|Full Text »|PDF »
Unexpected Role of TRPC6 Channel in Familial Nephrotic Syndrome: Does It Have Clinical Implications?.
M. P. Winn, N. Daskalakis, R. F. Spurney, and J. P. Middleton (2006)
J. Am. Soc. Nephrol.
17, 378-387
|Full Text »|PDF »
Activation of G{alpha}q-Coupled Signaling Pathways in Glomerular Podocytes Promotes Renal Injury.
L. Wang, T. A. Fields, K. Pazmino, Q. Dai, J. L. Burchette, D. N. Howell, T. M. Coffman, and R. F. Spurney (2005)
J. Am. Soc. Nephrol.
16, 3611-3622
|Abstract »|Full Text »|PDF »
Mutational and Biological Analysis of {alpha}-Actinin-4 in Focal Segmental Glomerulosclerosis.
A. Weins, P. Kenlan, S. Herbert, T. C. Le, I. Villegas, B. S. Kaplan, G. B. Appel, and M. R. Pollak (2005)
J. Am. Soc. Nephrol.
16, 3694-3701
|Abstract »|Full Text »|PDF »
Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies.
M. Freichel, R. Vennekens, J. Olausson, S. Stolz, S. E Philipp, P. Weissgerber, and V. Flockerzi (2005)
J. Physiol.
567, 59-66
|Abstract »|Full Text »|PDF »
