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Open Access 01-11-2009 | Review

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

Authors: M. M. Löwik, P. J. Groenen, E. N. Levtchenko, L. A. Monnens, L. P. van den Heuvel

Published in: European Journal of Pediatrics | Issue 11/2009

Abstract

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction.

Agarwal AK, Zhou XJ, Hall RK et al (2006) Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med 54:208–13PubMedCrossRef

Artero M, Biava C, Amend W et al (1992) Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med 92:375–383PubMedCrossRef

Artero ML, Sharma R, Savin VJ, Vincenti F (1994) Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 23:574–581PubMed

Ballermann BJ (2005) Glomerular endothelial cell differentiation. Kidney Int 67:1668–1671PubMedCrossRef

Balreira A, Gaspar P, Caiola D et al (2008) A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome. Hum Mol Genet 17:2238–2243PubMedCrossRef

Barbaux S, Niaudet P, Gubler MC et al (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470PubMedCrossRef

Barisoni L, Kopp JB (2003) Update in podocyte biology: putting one’s best foot forward. Curr Opin Nephrol Hypertens 12:251–258PubMedCrossRef

Barker DF, Hostikka SL, Zhou J et al (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227PubMedCrossRef

Berkovic SF, Dibbens LM, Oshlack A et al (2008) Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet 82:673–684PubMedCrossRef

10.

Bertelli R, Ginevri F, Caridi G et al (2003) Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Am J Kidney Dis 41:1314–1321PubMedCrossRef

11.

Boerkoel CF, Takashima H, John J et al (2002) Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat Genet 30:215–220PubMedCrossRef

12.

Bongers EM, Gubler MC, Knoers NV (2002) Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 17:703–712PubMedCrossRef

13.

Boute N, Gribouval O, Roselli S et al (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354PubMedCrossRef

14.

Bruening W, Bardeesy N, Silverman BL et al (1992) Germline intronic and exonic mutations in the Wilms’ tumour gene (WT1) affecting urogenital development. Nat Genet 1:144–148PubMedCrossRef

15.

Bwerdeli A, Mir S, Yavascan O et al (2007) NPSHS2 (podocin) mutations in Turkish children with idiopathic nephrotic syndrome. Pediatr Nephrol 22:2031–2040CrossRef

16.

Caridi G, Bertelli R, Scolari F (2004) Podocin mutations in sporadic focal-segmental glomerulosclerosis occurring in adulthood. Kidney Int 64:365CrossRef

17.

Caridi G, Perfumo F, Ghiggeri GM (2005) NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms. Pediatr Res 57:54R–61RPubMedCrossRef

18.

Cheong HI, Chae JH, Kim JS et al (1999) Hereditary glomerulopathy associated with a mitochondrial tRNA(Leu) gene mutation. Pediatr Nephrol 13:477–480PubMedCrossRef

19.

Cormont M, Meton I, Mari M et al (2003) CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl. Traffic 4:97–112PubMedCrossRef

20.

D’Agati V (2003) Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 23:117–134PubMedCrossRef

21.

D’Agati VD (2008) The spectrum of focal segmental glomerulosclerosis: new insights. Curr Opin Nephrol Hypertens 17:271–281PubMedCrossRef

22.

D’Agati VD, Fogo AB, Bruijn JA, Jennette JC (2004) Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 43:368–382PubMedCrossRef

23.

Dall’Amico R, Ghiggeri G, Carraro M et al (1999) Prediction and treatment of recurrent focal segmental glomerulosclerosis after renal transplantation in children. Am J Kidney Dis 34:1048–1055PubMedCrossRef

24.

Dandapani SV, Sugimoto H, Matthews BD et al (2007) Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem 282:467–477PubMedCrossRef

25.

Denamur E, Bocquet N, Mougenot B et al (1999) Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. J Am Soc Nephrol 10:2219–2223PubMed

26.

Diomedi-Camassei F, Di Giandomenico S, Santorelli FM et al (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780PubMedCrossRef

27.

Doleris LM, Hill GS, Chedin P et al (2000) Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int 58:1851–1858PubMedCrossRef

28.

Dustin ML, Olszowy MW, Holdorf AD et al (1998) A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94:667–677PubMedCrossRef

29.

Elizondo LI, Cho KS, Zhang W et al (2009) Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotype correlation. J Med Genet 46:49–59PubMedCrossRef

30.

Faul C, Donelly M, Merscher-Gomez S et al (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nature Medicine 14:931–938PubMedCrossRef

31.

Freichel M, Vennekens R, Olausson J et al (2005) Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies. J Physiol 567:59–66PubMedCrossRef

32.

Gbadegesin R, Hinkes BG, Hoskins BE et al (2008) Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291–1297PubMedCrossRef

33.

Gessler M, Poustka A, Cavenee W et al (1990) Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778PubMedCrossRef

34.

Ghiggeri GM, Caridi G, Magrini U et al (2003) Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome). Am J Kidney Dis 41:95–104PubMedCrossRef

35.

Goldenberg A, Ngoc LH, Thouret MC et al (2005) Respiratory chain deficiency presenting as congenital nephrotic syndrome. Pediatr Nephrol 20:465–469PubMed

36.

Graham S, Ding M, Sours-Brothers S et al (2007) Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes. Am J Physiol Renal Physiol 293:F1381–F1390PubMedCrossRef

37.

Guery B, Choukroun G, Noel LH et al (2003) The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA (Leu) gene mutation. J Am Soc Nephrol 14:2099–2108PubMedCrossRef

38.

Haber DA, Buckler AJ, Glaser T et al (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms’ tumor. Cell 61:1257–1269PubMedCrossRef

39.

Haber DA, Sohn RL, Buckler AJ (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A 88:9618–9622PubMedCrossRef

40.

Hasselbacher K, Wiggins RC, Matejas V et al (2006) Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int 70:1008–1012PubMedCrossRef

41.

Hattori M, Akioka Y, Chikamoto H et al (2008) Increase of integrin-linked kinase activity in cultured podocytes upon stimulation with plasma from patients with recurrent FSGS. Am J Transplant 8:1550–1556PubMedCrossRef

42.

Hinkes BG, Mucha B, Vlangos CN et al (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1 and LAMB2). Pediatrics 119:e907–919PubMedCrossRef

43.

Hinkes B, Wiggins RC, Gbadegesin R et al (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405PubMedCrossRef

44.

Hotta O, Inoue CN, Miyabayashi S (2001) Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int 59:1236–1243PubMedCrossRef

45.

Hsu HH, Hoffmann S, Endlich N et al (2007) Mechanism of angiotensin signaling on cytoskeleton of podocytes. J Mol Med 86:1379–1394CrossRef

46.

Huber TB, Hartleben B, Kim J et al (2003) Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 23:4917–4928PubMedCrossRef

47.

Huber TB, Kottgen M, Schilling B et al (2001) Interaction with podocin facilitates nephrin signaling. J Biol Chem 276:41543–41546PubMedCrossRef

48.

Huber TB, Kwoh C, Wu H et al (2006) Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. J Clin Invest 116:1337–1345PubMedCrossRef

49.

Huber TB, Simons M, Hartleben B et al (2003) Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet 12:3397–3405PubMedCrossRef

50.

Ilagan MX, Kopan R (2007) SnapShot: notch signaling pathway. Cell 128:1246PubMedCrossRef

51.

Jacob KN, Garg A (2006) Laminopathies: multisystem dystrophy syndromes. Mol Genet Metab 87:289–302PubMedCrossRef

52.

Jansen JJ, Maassen JA, van der Woude FJ et al (1997) Mutation in mitochondrial tRNA(Leu(UUR)) gene associated with progressive kidney disease. J Am Soc Nephrol 8:1118–1124PubMed

53.

Jeanpierre C, Denamur E, Henry I et al (1998) Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet 62:824–833PubMedCrossRef

54.

Jeansson M, Haraldsson B (2006) Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier. Am J Physiol Renal Physiol 290:F111–116PubMedCrossRef

55.

Kaplan JM, Kim SH, North KN et al (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256PubMedCrossRef

56.

Karamatic Crew V, Poole J, Long S et al (2008) Two MER2-negative individuals with the same novel CD151 mutation and evidence for clinical significance of anti-MER2. Transfusion 48:1912–1916PubMedCrossRef

57.

Karle SM, Uetz B, Ronner V et al (2002) Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:388–393PubMed

58.

Kershaw DB, Sedman AB, Kelsch RC, Bunchman TE (1994) Recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients: successful treatment with oral cyclophosphamide. Clin Transplant 8:546–549PubMed

59.

Kestila M, Lenkkeri U, Mannikko M et al (1998) Positionally cloned gene for a novel glomerular protein–nephrin is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582PubMedCrossRef

60.

Kim JM, Wu H, Green G et al (2003) CD2-associated protein haplo-insufficiency is linked to glomerular disease susceptibility. Science 300:1298–1300PubMedCrossRef

61.

Kirsch KH, Georgescu MM, Ishimaru S, Hanafusa H (1999) CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc Natl Acad Sci U S A 96:6211–6216PubMedCrossRef

62.

Klamt B, Koziell A, Poulat F et al (1998) Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet 7:709–714PubMedCrossRef

63.

Kobayashi S, Sawano A, Nojima Y et al (2004) The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1). FASEB J 18:929–931PubMed

64.

Kohsaka T, Tagawa M, Takekoshi Y et al (1999) Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat 14:466–470PubMedCrossRef

65.

Kopp JB, Smith MW, Nelson GW et al (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175–1184PubMedCrossRef

66.

Kos CH, Le TC, Sinha S et al (2003) Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest 111:1683–1690PubMed

67.

Koziell A, Grech V, Hussain S et al (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 11:379–388PubMedCrossRef

68.

Kretzler M (2002) Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech 57:247–253PubMedCrossRef

69.

Kurogouchi F, Oguchi T, Mawatari E et al (1998) A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol 18:551–556PubMedCrossRef

70.

Laakkonen H, Lönnqvist T, Uusimaa J et al (2006) Muscular dystonia and athetosis in six patients with congenital nephrotic syndrome of the Finnish type (NPHS1). Pediatr Nephrol 21:182–189PubMedCrossRef

71.

Lehtonen S, Zhao F, Lehtonen E (2002) CD2-associated protein directly interacts with the actin cytoskeleton. Am J Physiol Renal Physiol 283:F734–743PubMed

72.

Levidiotis V, Power DA (2005) New insights into the molecular biology of the glomerular filtration barrier and associated disease. Nephrology (Carlton) 10:157–166CrossRef

73.

Little M, Holmes G, Bickmore W et al (1995) DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum Mol Genet 4:351–358PubMedCrossRef

74.

Little M, Wells C (1997) A clinical overview of WT1 gene mutations. Hum Mutat 9:209–225PubMedCrossRef

75.

Liu XL, Done SC, Yan K et al (2004) Defective trafficking of nephrin missense mutants rescued by a chemical chaperone. J Am Soc Nephrol 15:1731–1738PubMedCrossRef

76.

Löwik M, Levtchenko E, Westra D et al (2008) Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis. Nephrol Dial Transplant 23:3146–3151PubMedCrossRef

77.

Löwik MM, Groenen PJ, Pronk I et al (2007) Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. Kidney Int 72:1198–1203PubMedCrossRef

78.

Lopez-Martin JM, Salviati L, Trevisson E et al (2007) Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet 16:1091–1097PubMedCrossRef

79.

Lücke T, Franke D, Clewing JM et al (2006) Schimke versus non-Schimke chronic kidney disease: an anthropometric approach. Pediatrics 118:e400–407PubMedCrossRef

80.

Lynch DK, Winata SC, Lyons RJ et al (2003) A cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem 278:21805–21813PubMedCrossRef

81.

Marini M, Bruschi M, Pecci A et al (2006) Non-muscle myosin heavy chain IIA and IIB interact and co-localize in living cells: relevance for MYH9-related disease. Int J Mol Med 17:729–736PubMed

82.

Mathieson PW (2008) Proteinuria and immunity—an overstated relationship? N Engl J Med 359:2492–2494PubMedCrossRef

83.

McTaggart SJ (2005) Childhood urinary conditions. Aust Fam Physician 34:937–941PubMed

84.

McTaggart SJ, Algar E, Chow CW et al (2001) Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol 16:335–339PubMedCrossRef

85.

Meyrier A (2005) Treatment of focal segmental glomerulosclerosis. Expert Opin Pharmacoth 6:1539–1549CrossRef

86.

Michaud JL, Lemieux LI, Dube M et al (2003) Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4. J Am Soc Nephrol 14:1200–1211PubMedCrossRef

87.

Miner JH, Morello R, Andrews KL et al (2002) Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. J Clin Invest 109:1065–1072PubMed

88.

Moller CC, Wei C, Altintas MM et al (2007) Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol 18:29–36PubMedCrossRef

89.

Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 358:2849–2850PubMedCrossRef

90.

Morrison AA, Viney RL, Saleem MA, Ladomery MR (2008) New insights into the function of the Wilms tumor suppressor gene WT1 in podocytes. Am J Physiol Renal Physiol 295:F12–F17PubMedCrossRef

91.

Nakajo A, Khoshnoodi J, Takenaka H et al (2007) Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance. J Am Soc Nephrol 18:2554–2564PubMedCrossRef

92.

Nakamura S, Yoshinari M, Doi Y et al (1999) Renal complications in patients with diabetes mellitus associated with an A to G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Diabetes Res Clin Pract 44:183–189PubMedCrossRef

93.

Niaudet P (2004) Steroid-resistant idiopathic nephrotic syndrome in children. In: Niaudet P, Avner ED, Harmon WE (eds.) Pediatric Nephrology, Blackwell, Philadelphia, pp 557–573

94.

Niranjan T, Bielesz B, Gruenwald A et al (2008) The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 14:290–298PubMedCrossRef

95.

Nishibori Y, Liu L, Hosoyamada M et al (2004) Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane. Kidney Int 66:1755–1765PubMedCrossRef

96.

Orikasa M, Matsui K, Oite T, Shimizu F (1988) Massive proteinuria induced in rats by a single intravenous injection of a monoclonal antibody. J Immunol 141:807–814PubMed

97.

Patrakka J, Ruotsalainen V, Reponen P et al (2002) Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 73:394–403PubMedCrossRef

98.

Pavenstädt H, Kriz W, Kretzler M (2003) Cell biology of the glomerular podocyte. Physiol Rev 83:253–307PubMed

99.

Pelletier J, Bruening W, Kashtan CE et al (1991) Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447PubMedCrossRef

100.

Pereira AC, Pereira AB, Mota GF et al (2004) NPHS2 R229Q functional variant is associated with micro-albuminuria in the general population. Kidney Int 65:1026–1030PubMedCrossRef

101.

Philippe A, Nevo F, Esquivel EL, Reklaityte D et al (2008) Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:1871–1878PubMedCrossRef

102.

Piechota J, Mroczek K, Bartnik E (2001) MELAS as an example of a mitochondrial disease. J Appl Genet 42:351–358PubMedCrossRef

103.

Putaala H, Soininen R, Kilpelainen P et al (2001) The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet 10:1–8PubMedCrossRef

104.

Quinzii C, Naini A, Salviati L et al (2006) A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78:345–349PubMedCrossRef

105.

Reczek D, Schwake M, Schröder J et al (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131:770–783PubMedCrossRef

106.

Reiser J, Polu KR, Moller CC et al (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37:739–744PubMedCrossRef

107.

Riccio A, Medhurst AD, Mattei C et al (2002) mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res Mol Brain Res 109:95–104PubMedCrossRef

108.

Rodewald R, Karnovsky MJ (1974) Porous substructure of the glomerular slit diaphragm in the rat and mouse. J Cell Biol 60:423–433PubMedCrossRef

109.

Roselli S, Gribouval O, Boute N et al (2002) Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 160:131–139PubMed

110.

Roselli S, Heidet L, Sich M et al (2004) Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 24:550–560PubMedCrossRef

111.

Roselli S, Moutkine I, Gribouval O et al (2004) Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations. Traffic 5:37–44PubMedCrossRef

112.

Ruf RG, Lichtenberger A, Karle SM et al (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732PubMedCrossRef

113.

Sachs N, Kreft M, van den Bergh Weerman MA et al (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175:33–39PubMedCrossRef

114.

Sartelet H, Pietrement C, Noel LH et al (2008) Collapsing glomerulopathy in Galloway-Mowat syndrome: a case report and review of the literature. Pathol Res Pract 204:401–406PubMedCrossRef

115.

Savin VJ, Sharma M, McCarthy ET et al (2008) Cardiotrophin like cytokine-1: candidate for the focal segmental sclerosis permeability factor. J Am Soc Nephrol 19:59A F-FC260CrossRef

116.

Savin VJ, Sharma R, Sharma M et al (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878–883PubMedCrossRef

117.

Scaglia F, Vogel H, Hawkins EP et al (2003) Novel homoplasmic mutation in the mitochondrial tRNATyr gene associated with atypical mitochondrial cytopathy presenting with focal segmental glomerulosclerosis. Am J Med Genet A 123:172–178CrossRef

118.

Schiffer M, Mundel P, Shaw AS, Böttinger EP (2004) A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem 279:37004–37012PubMedCrossRef

119.

Schlöndorff JS, Pollak MR (2006) TRPC6 in glomerular health and disease: what we know and what we believe. Semin Cell Dev Biol 17:667–674PubMedCrossRef

120.

Schmiedel J, Jackson S, Schafer J, Reichmann H (2003) Mitochondrial cytopathies. J Neurol 250:267–277PubMedCrossRef

121.

Schwarz K, Simons M, Reiser J et al (2001) Podocin, a raft-associated component of the glomerular slit diaphragm interacts with CD2AP and nephrin. J Clin Invest 108:1621–1629PubMed

122.

Sellin L, Huber TB, Gerke P et al (2003) NEPH1 defines a novel family of podocin interacting proteins. FASEB J 17:115–117PubMed

123.

Seri M, Savino M, Bordo D et al (2002) Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene. Hum Genet 110:182–186PubMedCrossRef

124.

Shih NY, Li J, Cotran R et al (2001) CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol 159:2303–2308PubMed

125.

Shih NY, Li J, Karpitskii V et al (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315PubMedCrossRef

126.

Simons M, Schwarz K, Kriz W et al (2001) Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol 159:1069–1077PubMed

127.

Sours S, Du J, Chu S et al (2006) Expression of canonical transient receptor potential (TRPC) proteins in human glomerular mesangial cells. Am J Physiol Renal Physiol 290:F1507–F1515PubMedCrossRef

128.

Srivastava T, Simon SD, Alon US (1999) High incidence of focal segmental glomerulosclerosis in nephrotic syndrome of childhood. Pediatr Nephrol 13:13–18PubMedCrossRef

129.

St John PL, Abrahamson DR (2001) Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and -11 chains. Kidney Int 60:1037–1046PubMedCrossRef

130.

Taniike M, Fukushima H, Yanagihara I et al (1992) Mitochondrial tRNA(Ile) mutation in fatal cardiomyopathy. Biochem Biophys Res Commun 15:47–53CrossRef

131.

Thomas DB, Franceschini N, Hogan SL et al (2006) Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 69:920–926PubMedCrossRef

132.

Tsukaguchi H, Sudhakar A, Le TC (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 110:1659–1666PubMed

133.

Verma R, Wharram B, Kovari I et al (2003) Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin. J Biol Chem 278:20716–20723PubMedCrossRef

134.

Vooijs M, Ong CT, Hadland B et al (2007) Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 134:535–544PubMedCrossRef

135.

Wagner KD, Wagner N, Schedl A (2003) The complex life of WT1. J Cell Sci 116:1653–1658PubMedCrossRef

136.

Wada T, Pippin JW, Nangaku M et al (2008) Dexamethasone’s prosurvival benefits in podocytes require extracellular signal-regulated kinase phosphorylation. Nephron Exp Nephrol 109:e8–e19PubMedCrossRef

137.

Wang SX, Ahola H, Palmen T et al (2001) Recurrence of nephrotic syndrome after transplantation in CNF is due to autoantibodies to nephrin. Exp Nephrol 9:327–331PubMedCrossRef

138.

Wang L, Flannery PJ, Rosenberg PB et al (2008) Gq-dependent signaling upregulates COX2 in glomerular podocytes. J Am Soc Nephrol 19:2108–2118PubMedCrossRef

139.

Weber S, Gribouval O, Esquivel EL et al (2004) NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66:571–579PubMedCrossRef

140.

Weins A, Kenlan P, Herbert S et al (2005) Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 16:3694–3701PubMedCrossRef

141.

Weins A, Schlondorff J, Nakamura F et al (2007) Disease-associated mutant alpha-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc Natl Acad Sci U S A 104:16080–16085PubMedCrossRef

142.

Winn MP, Conlon PJ, Lynn KL et al (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308:1801–1804PubMedCrossRef

143.

Woroniecki RP, Kopp JB (2007) Genetics of focal segmental glomerulosclerosis. Pediatr Nephrol 22:638–644PubMedCrossRef

144.

Yamagata K, Muro K, Usui J et al (2002) Mitochondrial DNA mutations in focal segmental glomerulosclerosis lesions. J Am Soc Nephrol 13:1816–1823PubMedCrossRef

145.

Yasukawa T, Suzuki T, Ueda T et al (2000) Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem 275:4251–4257PubMedCrossRef

146.

Zenker M, Aigner T, Wendler O et al (2004) Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 13:2625–2632PubMedCrossRef

147.

Zivičnjak M, Franke D, Zenker M et al (2009) SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome. Pediatr Res 65:564–568PubMedCrossRef

148.

Nevo F, Machuca EA, Gribouval O et al. (2008) Abstract J Am Soc Nephrol

Title: Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review
Authors: M. M. Löwik
P. J. Groenen
E. N. Levtchenko
L. A. Monnens
L. P. van den Heuvel
Publication date: 01-11-2009
Publisher: Springer-Verlag
Published in: European Journal of Pediatrics / Issue 11/2009
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI: https://doi.org/10.1007/s00431-009-1017-x

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Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

Abstract

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Abstract

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