INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.
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Ошибки и ограничения
История · было → стало
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Boyer Olivia, Nevo Fabien, Plaisier Emmanuelle, Funalot Benoit, Gribouval Olivier, Benoit Geneviève, Huynh Cong Evelyne, Arrondel Christelle, Tête Marie-Josèphe, Montjean Rodrick, Richard Laurence, Karras Alexandre, Pouteil-Noble Claire, Balafrej Leila, Bonnardeaux Alain, Canaud Guillaume, Charasse Christophe, Dantal Jacques, Deschenes Georges, Deteix Patrice, Dubourg Odile, Petiot Philippe, Pouthier Dominique, Leguern Eric, Guiochon-Mantel Anne, Broutin Isabelle, Gubler Marie-Claire, Saunier Sophie, Ronco Pierre, Vallat Jean-Michel, Alonso Miguel Angel, Antignac Corinne, Mollet Géraldine
Аннотация
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.).