title: INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.
abstract: 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.).
authors.affiliation: INSERM Unité 983, Service de Néphrologie Pédiatrique, Hôpital Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.forename: Fabien
authors.initials: F
authors.lastname: Nevo
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Plaisier
authors.forename: Benoit
authors.initials: B
authors.lastname: Funalot
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Geneviève
authors.initials: G
authors.lastname: Benoit
authors.forename: Evelyne
authors.initials: E
authors.lastname: Huynh Cong
authors.forename: Christelle
authors.initials: C
authors.lastname: Arrondel
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Tête
authors.forename: Rodrick
authors.initials: R
authors.lastname: Montjean
authors.forename: Laurence
authors.initials: L
authors.lastname: Richard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
authors.forename: Claire
authors.initials: C
authors.lastname: Pouteil-Noble
authors.forename: Leila
authors.initials: L
authors.lastname: Balafrej
authors.forename: Alain
authors.initials: A
authors.lastname: Bonnardeaux
authors.forename: Guillaume
authors.initials: G
authors.lastname: Canaud
authors.forename: Christophe
authors.initials: C
authors.lastname: Charasse
authors.forename: Jacques
authors.initials: J
authors.lastname: Dantal
authors.forename: Georges
authors.initials: G
authors.lastname: Deschenes
authors.forename: Patrice
authors.initials: P
authors.lastname: Deteix
authors.forename: Odile
authors.initials: O
authors.lastname: Dubourg
authors.forename: Philippe
authors.initials: P
authors.lastname: Petiot
authors.forename: Dominique
authors.initials: D
authors.lastname: Pouthier
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Broutin
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Alonso
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mollet
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics*; D002648:Child; D005260:Female; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology*; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009185:Myelin Proteins / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D010641:Phenotype; D011510:Proteolipids / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000199:Actins; D000080865:Formins; C546959:INF2 protein, human; C569026:MAL protein, human; C569027:Mal protein, mouse; D026901:Membrane Transport Proteins; D008840:Microfilament Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids