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The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

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Abstract

Thin-basement-membrane nephropathy (TBMN) is characterized by persistent dysmorphic hematuria, and the presence of proteinuria is a risk factor for renal impairment. TBMN is often due to mutations in the COL4A3 and COL4A4 genes, and this study determined whether additional mutations in genes encoding other structures in the glomerular filtration barrier contributed to the development of proteinuria. Fifty-six unrelated individuals with TBMN including 18 (32%) with proteinuria ≥ 300 mg/L and ten (18%) with proteinuria ≥ 500 mg/L were studied. Deoxyribonucleic acid (DNA) was screened for NPHS2 mutations and variants (R138Q and P375L) using single-stranded conformational analysis (SSCA) and for the R229Q mutation by sequencing. DNA was also screened for ACTN4 mutations. R229Q was more common in patients with TBMN and proteinuria ≥ 500 mg/L (p < 0.05), and a possible NPHS2 mutation (671G>A, R224H) was identified in one patient with proteinuria 700 mg/L. No other NPHS2 variants correlated with proteinuria, and no ACTN4 mutations were found. Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS). The early demonstration of R229Q in individuals with TBMN may indicate those at increased risk of proteinuria and renal impairment.

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Acknowledgments

This work was supported in part by the National Health and Medical Research Council of Australia and Kidney Health Australia. This work was presented as a poster at the Annual Meeting of the American Society of Nephrology, 2003, and at the 6th International Podocyte Conference 2006.

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Authors and Affiliations

  1. Department of Medicine (Austin Health/Northern Health), The Northern Hospital, The University of Melbourne, Epping, VIC 3076, Australia

    Stephen Tonna, Yan Yan Wang, Lin Rigby & Judy Savige

  2. Box Hill Hospital, Box Hill, 3128, Australia

    Diane Wilson

  3. Genomic Disorders Research Centre, St Vincent’s Hospital, Fitzroy, 3065, Australia

    Tania Tabone & Richard Cotton

  4. The University of Melbourne (Northern Health), The Northern Hospital, 185 Cooper St, Epping, VIC 3076, Australia

    Judy Savige

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  1. Stephen Tonna
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  2. Yan Yan Wang
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  3. Diane Wilson
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  4. Lin Rigby
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  6. Richard Cotton
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  7. Judy Savige
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Correspondence to Judy Savige.

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Tonna, S., Wang, Y.Y., Wilson, D. et al. The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy. Pediatr Nephrol 23, 2201–2207 (2008). https://doi.org/10.1007/s00467-008-0934-7

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  • DOI: https://doi.org/10.1007/s00467-008-0934-7

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