INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy

N Engl J Med. 2011 Dec 22;365(25):2377-88. doi: 10.1056/NEJMoa1109122.


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.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adolescent
  • Adult
  • Age of Onset
  • Animals
  • Charcot-Marie-Tooth Disease / complications
  • Charcot-Marie-Tooth Disease / genetics*
  • Child
  • Female
  • Formins
  • Glomerulosclerosis, Focal Segmental / etiology*
  • Heterozygote
  • Humans
  • Kidney / metabolism*
  • Male
  • Membrane Transport Proteins / metabolism
  • Mice
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Mutation
  • Myelin Proteins / metabolism
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Phenotype
  • Proteolipids / metabolism
  • Schwann Cells / metabolism*
  • Young Adult


  • Actins
  • Formins
  • INF2 protein, human
  • MAL protein, human
  • Mal protein, mouse
  • Membrane Transport Proteins
  • Microfilament Proteins
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Proteolipids