Background

Charcot–Marie–Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot–Marie–Tooth neuropathy associated with FSGS.

Methods

We performed direct genotyping of INF2 in 16 index patients with Charcot–Marie–Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted.

Results

We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot–Marie–Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2–MAL–CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42.

Conclusions

INF2 mutations appear to cause many cases of FSGS-associated Charcot–Marie–Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.)

Supported by grants from the Association pour l'Utilisation du Rein Artificiel (to Dr. Antignac), Association Française contre les Myopathies (ANR-08-GENOPAT-017-01, to Dr. Antignac), Agence Nationale de la Recherche (PodoNet project number ANR-07-E-RARE-011-01 in the ERA-Net Consortium [JTC2007], to Dr. Antignac, and ANR-06-MRAR-024-01, to Dr. Leguern), Fondation pour la Recherche Médicale (project number DMP 2010-11-20-386, to Dr. Antignac, and doctoral funding, to Dr. Boyer), Association des Malades du Syndrome Néphrotique (to Dr. Mollet), Fonds de la Recherche en Santé du Québec (Fellowship Training Award to Dr. Benoit), and Ministerio de Ciencia e Innovación (BFU2009-07886 and CONSOLIDER COAT CSD2009-00016, to Dr. Alonso).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Scott J. Harvey for helpful discussions; Martin R. Pollak, Philippe Chavrier, and Christopher Carpenter for providing FLAG-INF2-WT, GFP-IQGAP1-WT, and HA-CDC42–Q61L plasmids, respectively; Bernard Zalc for providing MSC-80 cells; Olivier Dorseuil for providing the GST-PAK construct; Catherine Lacroix, Laure-Hélène Noël, and Dominique Nochy for providing histologic sections; Nicolas Goudin (of Plateau d'Imagerie Cellulaire, Institut Fédératif de Recherche Necker–Enfants Malades, Paris) for providing expert knowledge on confocal microscopy; Drs. Bommelaer, Clavelou, Campone, Quérin, Rieu, Rouhart, Sarret, and Squalli Houssaini for providing medical information about their patients and the families who participated in this study; and the NHLBI Exome Sequencing Project (http://snp.gs.washington.edu/EVS/) for providing exome variant cells for comparison.

Source Information

The authors' affiliations are listed in the appendix.

Address reprint requests to Dr. Antignac at INSERM U983, 6e étage, Tour Lavoisier, Hôpital Necker–Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France, or at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

Appendix

The authors' affiliations are as follows: INSERM Unité 983 (O.B., F.N., O.G., G.B., E.H.C., C. Arrondel, M.-J.T., R.M., M.-C.G., S.S., C. Antignac, G.M.), Unité 702 (E.P., P.R.), and Unité 975 (E.L.); Service de Néphrologie Pédiatrique (O.B.), Service de Transplantation et Soins Intensifs (G.C.), and Service de Génétique (C. Antignac), Hôpital Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP); Service de Néphrologie et Dialyses (E.P., P.R.), Hôpital Tenon, AP-HP; Service de Néphrologie (A.K.), Hôpital Européen Georges Pompidou, AP-HP; Service de Néphrologie Pédiatrique (G.D.), Hôpital Robert Debré, AP-HP; Institut de Myologie (O.D.), Hôpital Pitié–Salpêtrière, AP-HP; Université Paris Descartes, Sorbonne Paris Cité (O.B., F.N., O.G., E.H.C., C. Arrondel, M.-J.T., R.M., A.K., G.C., I.B., M.-C.G., S.S., C. Antignac, G.M.); Université Pierre et Marie Curie (E.P., E.L., P.R.); Université Paris Diderot (G.D.); Centre National de la Recherche Scientifique Unité 7225 (E.L.) and Laboratoire de Cristallographie et RMN Biologiques (I.B.) — all in Paris; Laboratoire et Service de Neurologie, Centre Hospitalier Universitaire (CHU) et Université de Limoges, Limoges (B.F., L.R., J.-M.V.); Université de Lyon (C.P.-N.), Service de Néphrologie, Centre Hospitalier Lyon-Sud (C.P.-N.), and Service de Neurologie, Hôpital de la Croix-Rousse (P.P.), Hospices Civils de Lyon — all in Lyon; Centre Hospitalier de Saint-Brieuc, Saint-Brieuc (C.C.); Service de Néphrologie et Immunologie Clinique, CHU Hôtel Dieu, Nantes (J.D.); CHU Gabriel Montpied, Université d'Auvergne, Clermont-Ferrand (P.D.); Génétique Moléculaire, Pharmacogénétique et Hormonologie, CHU Bicêtre, Université Paris-Sud, Le Kremlin-Bicêtre (A.G.-M.) — all in France; Service de Néphrologie Pédiatrique, CHU Sainte-Justine, Université de Montréal (G.B.); and Centre de Recherche Guy-Bernier, Hôpital Maisonneuve–Rosemont (A.B.) — both in Montreal; Centre de Néphrologie et d'Hémodialyse Riad, Rabat, Morocco (L.B.); Service de Néphrologie, Centre Hospitalier de Luxembourg, Luxemburg (D.P.); and Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas–Universidad Autónoma de Madrid, Madrid (M.A.A.).

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