Submission Details

In the context of an autosomal dominant, intermediate Charcot-Marie-Tooth (CMT) phenotype and concomitant focal segmental glomerulosclerosis (FSGS), INF2 was first described by Boyer and colleagues in a series of 12 families in 2011 (PMID: 22187985). To date, 25 missense mutations and 3 in-frame deletions, all clustering in the diaphanous inhibitory domain (DID), have been associated with neuropathy (PMIDs e.g.: 24174593, 24487800, 24750328, 25676889). De-novo mutations are common, and the disease phenotype is highly specific with always including a progressive nephrotic syndrome, sometimes even preceding the neuropathy diagnosis by several years. INF2 encodes a member of the diaphanous-related formin family, which is involved in remodeling of the actin cytoskeleton, in mitochondrial dynamics, and microtubule stabilization. It is expressed in human sural nerves (PMID: 22187985) and co-localizes with the myelin protein MAL (PMID: 22187985). In mouse Schwann and HeLa cells, different mutants resulted in a disturbed actin-INF2-colocalization in the perinuclear area, and in patient sural nerve specimens, filamentous actin accumulated in the intracellular space (PMID: 22187985). A constitutive activation of the DID domain resulted in a reduction of mitochondrial length in transfected U2OS cells (PMID: 23349293). Morpholino-knockdown of INF2 in zebrafish resulted in a dorsalized and curling gross phenotype, which was partially rescued by co-injection of human wildtype INF2, but not by several mutants (PMID: 26086034). In summary, strong clinical evidence, including a highly specific phenotype, the de-novo occurrence of co-segregating variants, and the absence of such variants in healthy control collectives, is supported by experimental data on gene and variant level and has been replicated over time. We therefore classify the gene-disease relationship of INF2 and autosomal dominant, intermediate CMT with FSGS as definitive.