Human Molecular Genetics, 2002, Vol. 11, No. 4 379-388
© 2002 Oxford University Press
Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration
Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, 1Paediatric Department, St Luke’s Hospital, Guardamangia, Malta, 2Biocenter and Department of Biochemistry, University of Oulu, Linnanmaa, 90570 Oulu, Finland and 3Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177, Stockholm, Sweden
Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To investigate the mechanisms by which mutations might cause glomerular protein leak, we analysed NPHS1/NPHS2 genotype/phenotype relationships in 41 non-Finnish CNF patients, four patients with congenital (onset 0 to 3 months) focal segmental glomerulosclerosis and five patients with possible SRN1 (onset 6 months to 2 years). We clarify the range of NPHS1 mutations in CNF, detecting mutation ‘hot-spots’ within the NPHS1 coding sequence. In addition, we describe a novel discordant CNF phenotype characterized by variable clinical severity, apparently influenced by gender. Moreover, we provide evidence that CNF may be genetically heterogeneous by detection of NPHS2 mutations in some CNF patients in whom NPHS1 mutations were not found. We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a ‘tri-allelic’ hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS). This may result from an epistatic gene interaction, and provides a rare example of multiple allelic hits being able to modify an autosomal recessive disease phenotype in humans. Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration.
+ To whom correspondence should be addressed. Tel: +44 207 242 9789; Fax: +44 207 404 6191; Email: a.koziell@ich.ucl.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Machuca, G. Benoit, and C. Antignac Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology Hum. Mol. Genet., October 15, 2009; 18(R2): R185 - R194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Shono, H. Tsukaguchi, A. Kitamura, R. Hiramoto, X.-S. Qin, T. Doi, and K. Iijima Predisposition to relapsing nephrotic syndrome by a nephrin mutation that interferes with assembly of functioning microdomains Hum. Mol. Genet., August 15, 2009; 18(16): 2943 - 2956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hussain, L. Romio, M. Saleem, P. Mathieson, M. Serrano, J. Moscat, M. Diaz-Meco, P. Scambler, and A. Koziell Nephrin Deficiency Activates NF-{kappa}B and Promotes Glomerular Injury J. Am. Soc. Nephrol., August 1, 2009; 20(8): 1733 - 1743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lowik, E. Levtchenko, D. Westra, P. Groenen, E. Steenbergen, J. Weening, M. Lilien, L. Monnens, and L. v. d. Heuvel Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3146 - 3151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Philippe, F. Nevo, E. L. Esquivel, D. Reklaityte, O. Gribouval, M.-J. Tete, C. Loirat, J. Dantal, M. Fischbach, C. Pouteil-Noble, et al. Nephrin Mutations Can Cause Childhood-Onset Steroid-Resistant Nephrotic Syndrome J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1871 - 1878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Lemley Yet More Ways to Skin a Cat: Nephrin Mutations outside the Neonatal Period J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1837 - 1838. [Full Text] [PDF]
|
|
|
|
 |
|
 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 Nephrin Is Critical for the Action of Insulin on Human Glomerular Podocytes Diabetes, April 1, 2007; 56(4): 1127 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Woolf Renal Hypoplasia and Dysplasia: Starting to Put the Puzzle Together J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2647 - 2649. [Full Text] [PDF]
|
|
|
|
|
|
Y. Zuo, T. Matsusaka, J. Zhong, J. Ma, L.-j. Ma, Z. Hanna, P. Jolicoeur, A. B. Fogo, and I. Ichikawa HIV-1 Genes vpr and nef Synergistically Damage Podocytes, Leading to Glomerulosclerosis J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2832 - 2843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. VanDeVoorde, D. Witte, J. Kogan, and J. Goebel Pierson Syndrome: A Novel Cause of Congenital Nephrotic Syndrome Pediatrics, August 1, 2006; 118(2): e501 - e505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tryggvason, J. Patrakka, and J. Wartiovaara Hereditary proteinuria syndromes and mechanisms of proteinuria. N. Engl. J. Med., March 30, 2006; 354(13): 1387 - 1401. [Full Text] [PDF]
|
|
|
|
|
|
Y. Frishberg, S. Feinstein, C. Rinat, R. Becker-Cohen, I. Lerer, A. Raas-Rothschild, B. Ferber, and A. Nir The Heart of Children with Steroid-Resistant Nephrotic Syndrome: Is It All Podocin? J. Am. Soc. Nephrol., January 1, 2006; 17(1): 227 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yu, J. Ding, J. Huang, Y. Yao, H. Xiao, J. Zhang, J. Liu, and J. Yang Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children Nephrol. Dial. Transplant., May 1, 2005; 20(5): 902 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zenker, T. Aigner, O. Wendler, T. Tralau, H. Muntefering, R. Fenski, S. Pitz, V. Schumacher, B. Royer-Pokora, E. Wuhl, et al. Human laminin {beta}2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities Hum. Mol. Genet., November 1, 2004; 13(21): 2625 - 2632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. L. Liu, S. C. Done, K. Yan, P. Kilpelainen, T. Pikkarainen, and K. Tryggvason Defective Trafficking of Nephrin Missense Mutants Rescued by a Chemical Chaperone J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1731 - 1738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Benzing Signaling at the Slit Diaphragm J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1382 - 1391. [Full Text] [PDF]
|
|
|
|
|
|
N. Katsanis The oligogenic properties of Bardet-Biedl syndrome Hum. Mol. Genet., April 1, 2004; 13(90001): R65 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Ruf, A. Lichtenberger, S. M. Karle, J. P. Haas, F. E. Anacleto, M. Schultheiss, I. Zalewski, A. Imm, E.-M. Ruf, B. Mucha, et al. Patients with Mutations in NPHS2 (Podocin) Do Not Respond to Standard Steroid Treatment of Nephrotic Syndrome J. Am. Soc. Nephrol., March 1, 2004; 15(3): 722 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roselli, L. Heidet, M. Sich, A. Henger, M. Kretzler, M.-C. Gubler, and C. Antignac Early Glomerular Filtration Defect and Severe Renal Disease in Podocin-Deficient Mice Mol. Cell. Biol., January 15, 2004; 24(2): 550 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Huber, M. Simons, B. Hartleben, L. Sernetz, M. Schmidts, E. Gundlach, M. A. Saleem, G. Walz, and T. Benzing Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains Hum. Mol. Genet., December 15, 2003; 12(24): 3397 - 3405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Caridi, R. Bertelli, M. Di Duca, M. Dagnino, F. Emma, A. Onetti Muda, F. Scolari, N. Miglietti, G. Mazzucco, L. Murer, et al. Broadening the Spectrum of Diseases Related to Podocin Mutations J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1278 - 1286. [Abstract] [Full Text] [PDF]
|
|