Intermediate Filament Diseases

Abstract and Commentary

Synopsis: Further research will be required to understand the pathogenesis of these disorders.

Source: Omary MB, et al. Intermediate Filaments Proteins and Their Associated Diseases. N Engl J Med. 2004;351: 2087-2100.

Microfilaments, intermediate filaments, and microtubules constitute the cytoskeletal fibrillary family of proteins. Intermediate filaments (IF) are the most abundant, encoded by at least 65 functional genes. Long, rope-like, coiled coils, IF are composed of 2 alpha-helices wound around each other, 310 to 352 amino acids in length, with linker regions of 8 to 17 amino acids connecting these coils to form longer segments. Phosphorylation, glycosylation, and transglutamination are among the modifications that regulate these filaments, which also interact with linkers, bundlers, chaperones, kinases, apoptosis-related proteins, and nuclear proteins. Filament organization, solubility, susceptibility to degradation, and formation of inclusion bodies may all be modified by these factors. Functionally, they provide the scaffolding necessary for cell integrity, protect against non-mechanical stress and apoptosis, and aid axonal and dendritic extension.

Desmin related myopathy, identified in 1998 as the first non-keratin intermediate filament disease, results in distal weakness, cardiac arrhythmias, and restrictive heart failure due to accumulation of desmin aggregates in cardiac and skeletal muscle cells. Gain-of-function mutations of alphaB-crystallin, a chaperone regulating various cytoplasmic IF, also results in desmin myopathy. Emery-Dreyfuss and limb-girdle muscular dystrophy are laminopathies resulting from lamin A and C gene mutations. Both comprise muscle weakness and cardiac conduction defects with the former including elbow and heel contractures. Lamin A and C gene mutations also result in axonal neuropathy, ie, Charcot-Marie-Tooth disease type 2B1, which may be caused by neurofilament gene mutations as well. Neurofilament light chain gene mutations are involved in Types 2E and 1F Charcot-Marie-Tooth disease, while neurofilament heavy chain mutations are considered a risk factor in the development of amyotrophic lateral sclerosis, though no definitive causative association has been established. Non-neurologic disorders involving IF gene mutations include diseases of the skin and epithelium (epidermolysis bullosa simplex), hair (monilethrix, a disorder comprising alopecia and fragile hair), corneal dystrophy, dilated cardiomyopathy, and Werner’s syndrome of premature aging and senescence.

Further research will be required to understand the pathogenesis of these disorders. Therapeutics remains supportive in nature, with no method available to directly address the underlying disorder. With elucidation of disease mechanisms, however, it is hoped that tailored treatments will become a reality.


Although composed of different proteins, intermediate filaments, microfilaments, and microtubules are in constant and intimate communication, with intermediate filament proteins serving as important components in mediating this cross-talk (Nat Rev Mol Cell Biol. 2004;5;601-613). Five distinct types of intermediate filament proteins are recognized: types I and II (keratins), type III (vimentin, desmin, glial fibrillary acidic protein, and peripherin), type IV (3 neurofilament subunits, NF-L, NF-M, and NF-H, nestin, syncoilin, and alpha-internexin), and type V (lamin A, its splice variant lamin C, lamin B1, and lamin B2). Extending radially from the nucleus through the cytoplasm and to the cell surface, intermediate filaments are ideally positioned to coordinate cytoskeletal cross-talk. Microtubule- and microfilament-based motility are crucial for the assembly and maintenance of this scaffolding, which in turn are regulated by intermediate filament phosphorylation and microtubule-associated proteins, including tau.

Functionally, intermediate filaments are differentially expressed at various stages of nerve cell development and regeneration, and their cytoskeletal crosstalk may be central to the determination and maintenance of the diverse cell shapes seen during these periods. Cell movement and cell division may similarly be controlled by intermediate filaments, given their role involving signaling pathways which regulate microtubule and microfilament function and organization. — Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.