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.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Urisarri, A.
Outeda, P.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Outeda, P.
Banet, J. F.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Banet, J. F.
Malaga, S.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Malaga, S.
Vallo, A.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Vallo, A.
Pena, A.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Pena, A.
Rodriguez do Forno, A.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Rodriguez do Forno, A.
Ubetagoyena, M.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Ubetagoyena, M.
Valenciano, B.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Valenciano, B.
Garcia-Nieto, V
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Garcia-Nieto, V
Fdez-Iglesias, J. L.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Fdez-Iglesias, J. L.
Gil, M.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Gil, M.
Ariceta, G.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
Ariceta, G.
Lens, X. M.
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Santiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, SpainSantiago de Compostela Univ Hosp, Nephrol Invest Lab, Santiago De Compostela, Spain
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Univ Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, FinlandUniv Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, Finland
Kaukinen, Anne
Kuusniemi, Arvi-Matti
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Univ Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, FinlandUniv Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, Finland
Kuusniemi, Arvi-Matti
Lautenschlager, Irmeli
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Univ Helsinki, Cent Hosp, Dept Virol, Helsinki, FinlandUniv Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, Finland
Lautenschlager, Irmeli
Jalanko, Hannu
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Univ Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, FinlandUniv Helsinki, Hosp Children & Adolescents & Biomed Helsinki, Helsinki 00029, Finland
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Iran Univ Med Sci, Dept Pediat, Ali Asghar Childrens Hosp, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Ghazanfari, Behzad
Fereshtehnejad, Seyed-Mohammad
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Iran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Fereshtehnejad, Seyed-Mohammad
Bakhshayesh, Masoomeh
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Iran Univ Med Sci, Dept Genet, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Bakhshayesh, Masoomeh
Hashemi, Mehrdad
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Univ Tehran Med Sci, Dept Genet, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Hashemi, Mehrdad
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Hoseini, Rozita
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Chalian, Majid
Salami, Arezoo
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Iran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Salami, Arezoo
Mehdipor, Leila
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Iran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran
Mehdipor, Leila
Rahiminia, Aysan
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Iran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, IranIran Univ Med Sci, Gifted & Talented Ctr, Med Student Res Comm, Tehran, Iran