title: Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy.
abstract: Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. PC2 is an intracellular calcium channel expressed in renal epithelial cells and in cardiomyocytes, and is thus hypothesized to modulate intracellular calcium signaling and affect cardiac function. Our first aim was to study cardiac function in a zebrafish model lacking PC2 (pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining the Mayo Clinic's ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM). Pkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD. This association was strongest in patients with PKD2 mutations. Our results demonstrate that PC2 modulates intracellular calcium cycling, contributing to the development of heart failure. In human subjects we found an association between ADPKD and IDCM and suggest that PKD mutations contribute to the development of heart failure.
authors: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors: Jere
authors: J
authors: Paavola
authors: Simon
authors: S
authors: Schliffke
authors: Sandro
authors: S
authors: Rossetti
authors: Ivana Y-T
authors: IY
authors: Kuo
authors: Shiaulou
authors: S
authors: Yuan
authors: Zhaoxia
authors: Z
authors: Sun
authors: Peter C
authors: PC
authors: Harris
authors: Vicente E
authors: VE
authors: Torres
authors: Barbara E
authors: BE
authors: Ehrlich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000503:physiopathology; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D050396:TRPP Cation Channels; D029961:Zebrafish Proteins; C547527:PKD2 protein, zebrafish
references: J Mol Biol. 2003 Jan 31;325(5):949-62
references: 12527301
references: Hum Mol Genet. 2003 Aug 1;12(15):1875-80
references: 12874107
references: J Am Soc Nephrol. 2005 Feb;16(2):299-304
references: 15647335
references: N Engl J Med. 1988 Oct 6;319(14):907-12
references: 3419455
references: J Am Coll Cardiol. 1998 Jan;31(1):195-201
references: 9426040
references: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17699-704
references: 16314583
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7906-10
references: 16672364
references: Science. 1996 May 31;272(5266):1339-42
references: 8650545
references: Comp Biochem Physiol B Biochem Mol Biol. 2009 Dec;154(4):443-8
references: 19755169
references: Prog Biophys Mol Biol. 2008 Jun-Jul;97(2-3):332-47
references: 18395246
references: Circ Res. 2000 Jul 7;87(1):8-11
references: 10884365
references: Lancet. 2007 Apr 14;369(9569):1287-1301
references: 17434405
references: Am J Physiol Renal Physiol. 2009 Nov;297(5):F1310-5
references: 19726544
references: J Am Soc Nephrol. 2006 Oct;17(10):2706-18
references: 16943304
references: Adv Chronic Kidney Dis. 2010 Mar;17(2):153-63
references: 20219618
references: Development. 2004 Aug;131(16):4085-93
references: 15269167
references: Circ Res. 2002 Oct 4;91(7):553-5
references: 12364380
references: Science. 2003 Feb 28;299(5611):1410-3
references: 12610310
references: Circulation. 1996 Mar 1;93(5):841-2
references: 8598070
references: Am J Physiol Heart Circ Physiol. 2002 Mar;282(3):H1047-54
references: 11834503
references: J Am Coll Cardiol. 2007 Nov 6;50(19):1896-904
references: 17980258
references: J Am Soc Nephrol. 1995 Jun;5(12):2048-56
references: 7579053
references: Circ Res. 2004 Apr 30;94(8):1083-90
references: 15016735
references: Kidney Int. 2009 Apr;75(8):848-55
references: 19165178
references: Am J Kidney Dis. 2001 Dec;38(6):1208-16
references: 11728952
references: Circ Res. 2012 Mar 30;110(7):968-77
references: 22374134
references: Am J Kidney Dis. 1998 Dec;32(6):970-5
references: 9856512
references: Nat Genet. 2000 Jan;24(1):75-8
references: 10615132
references: Dis Model Mech. 2009 Jan-Feb;2(1-2):18-22
references: 19132116
references: J Am Coll Cardiol. 2006 Jan 17;47(2):269-81
references: 16412847
references: Cardiovasc Res. 2003 Apr 1;58(1):76-88
references: 12667948
references: J Am Soc Nephrol. 2008 Jul;19(7):1342-51
references: 18417723
references: Biochem Biophys Res Commun. 2001 Mar 23;282(1):341-50
references: 11264013
references: J Mol Cell Cardiol. 2010 Jan;48(1):161-71
references: 19747484
references: J Am Soc Nephrol. 2007 Jul;18(7):2143-60
references: 17582161
references: Circulation. 1989 Sep;80(3):564-72
references: 2766509
references: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6454-9
references: 17404231
references: Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H709-18
references: 10924070
references: Acta Physiol (Oxf). 2010 Jul 1;199(3):257-76
references: 20331541
references: J Cell Sci. 2006 Apr 1;119(Pt 7):1383-95
references: 16537653
references: Biochem Biophys Res Commun. 2004 Oct 1;322(4):1364-73
references: 15336985
references: Biochem Biophys Res Commun. 2008 Sep 12;374(1):143-6
references: 18602892
references: Kidney Int. 2005 Nov;68(5):2244-9
references: 16221225
references: Nat Genet. 1995 Jun;10(2):151-60
references: 7663510
references: J Am Coll Cardiol. 1998 Jan;31(1):186-94
references: 9426039
references: Nat Cell Biol. 2002 Mar;4(3):191-7
references: 11854751
references: J Am Soc Nephrol. 2003 Sep;14(9):2280-7
references: 12937304
references: Heart Fail Clin. 2008 Jan;4(1):13-21
references: 18313621
references: Cell Signal. 2007 Mar;19(3):444-53
references: 17084592
references: J Am Soc Nephrol. 1997 Aug;8(8):1292-7
references: 9259356
references: Trends Genet. 2002 Oct;18(10):491-4
references: 12350332
references: J Am Soc Nephrol. 2001 Jan;12(1):1-9
references: 11134244
references: Ann Med. 2007;39(2):91-107
references: 17453673
references: J Am Soc Nephrol. 2002 Jan;13(1):269-276
references: 11752048
references: Br Heart J. 1995 May;73(5):417-21
references: 7786655
references: Am J Kidney Dis. 2001 Oct;38(4):777-84
references: 11576881
references: N Engl J Med. 1994 Dec 8;331(23):1564-75
references: 7969328
references: Am J Physiol Regul Integr Comp Physiol. 2011 Jan;300(1):R56-66
references: 20926764
references: J Cell Physiol. 2002 Jan;190(1):1-6
references: 11807805