Intermediate filaments

In this issue of Neurology, Kulhenbäumer et al.1 describe novel mutations of the gene responsible for giant axonal neuropathy (GAN). GAN, a recessive multisystem disorder, presents with a variable phenotype that includes tightly curled hair, CNS involvement, and a progressive sensorimotor axonal neuropathy.2 GAN is an especially instructive reminder of the roles played by one class of cytoskeletal element: the intermediate filament. Intermediate filaments (IF) are a family of 10-nm diameter structures that interact with actin microfilaments (7 nm) and microtubules (24 nm) to form the cytoskeletal scaffolding in eukaryotic cells.3,4⇓ The most basic function of IF is to impart structural resilience to cells. This is exemplified in keratinocytes, where mutations in the major IF, keratin, result in bullous disorders of skin, including epidermolysis bullosa.3 In various instances it is now clear that abnormalities of IF or IF association proteins with disruption of the cytoskeletal network are pathogenic (table). Of special interest to neurologists is that mutations in desmin, the dominant IF in muscle, produce a recessive distal myopathy.3 In other filamentopathies, the primary defect is one of organization of the cytoskeletal network. Mutations in the plectin gene, a large IF association protein, produces a muscular dystrophy and epidermolysis bullosa.3

Neurofilaments …