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Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis

Nature Genetics volume 42, pages 72–76 (2010)Cite this article

A Corrigendum to this article was published on 01 April 2010

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Abstract

Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified that, when mutated, lead to inherited FSGS and/or the related nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal-dominant FSGS susceptibility on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent nonconservative missense mutations in INF2, which encodes a member of the formin family of actin-regulating proteins. These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.

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Figure 1: Pedigree diagrams of families FGBR and FGJN.
Figure 2: Summary of INF2 substitutions.
Figure 3: Histopathology.
Figure 4: INF2 expression.
Figure 5: Expression of INF2 variants.

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Change history

  • 05 February 2010

    In the version of this article initially published, Stephen J. Tonna was inadvertently omitted from the author list, and the fourth author (Hiroyasu Tsukaguchi) was missing one of his affiliations. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the many individuals who participated in this study; S. DePalma for help with linkage analysis; and J. Jacobs, K. Tucker, J. Holt, A. Acharya, R.Wiggins, R.Weir, J. Levine and many others for help with family ascertainment. This work was support by grants from the US National Institutes of Health (DK54931 to M.R.P., DK073091 to J.M.H., DK080947 to J.S.S. and GM069818 to H.N.H.) and the Clinical Investigator Training Program: Beth Israel Deaconess Medical School in collaboration with Pfizer Inc. and Merck and Co., the NephCure Foundation, and the Cole Pasqualucci Nephrotic Syndrome and FSGS Research fund (to E.J.B.). M.R.P. is an Established Investigator of the American Heart Association.

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Author notes

  1. Hiroyasu Tsukaguchi, Stephen J Tonna & Joel M Henderson

    Present address: Present addresses: Second Department of Internal Medicine, Kansai Medical University 10-15 Fumizono, Moriguchi, Osaka, Japan (H.T.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (S.J.T.) and Department of Pathology, Boston University Medical Center, Boston, Massachusetts, USA (J.M.H).,

Authors and Affiliations

  1. Renal Division, Children's Hospital, Boston, Massachusetts, USA

    Elizabeth J Brown

  2. Harvard Medical School, Boston, Massachusetts, USA

    Elizabeth J Brown, Johannes S Schlöndorff, Daniel J Becker, Hiroyasu Tsukaguchi, Stephen J Tonna & Martin R Pollak

  3. Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Johannes S Schlöndorff, Daniel J Becker, Hiroyasu Tsukaguchi, Stephen J Tonna, Andrea L Uscinski & Martin R Pollak

  4. Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, USA

    Henry N Higgs

  5. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Joel M Henderson

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Contributions

E.J.B. performed family and clinical ascertainment, performed and interpreted genetic linkage studies, performed mutational analysis and made DNA constructs. J.S.S. helped with study design and interpretation and performed INF2 expression studies. D.J.B. performed INF2 expression studies. H.T. performed genetic linkage studies. S.J.T. performed genotyping and sequencing analyses. A.L.U. helped with clinical ascertainment of the families. H.N.H. performed molecular modeling and assisted with data interpretation. J.M.H. performed histology studies. M.R.P. oversaw all aspects of study design and interpretation and wrote the manuscript with the assistance of the other authors.

Corresponding author

Correspondence to Martin R Pollak.

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Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Note (PDF 781 kb)

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Brown, E., Schlöndorff, J., Becker, D. et al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 42, 72–76 (2010). https://doi.org/10.1038/ng.505

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