"IF-pathies": a broad spectrum of intermediate filament-associated diseases

Abstract

Intermediate filaments (IFs) are encoded by the largest gene family among the three major cytoskeletal protein groups. Unique IF compliments are expressed in selective cell types, and this expression is reflected in their involvement, upon mutation, as a cause of or predisposition to more than 80 human tissue-specific diseases. This Review Series covers diseases and functional and structural aspects pertaining to IFs and highlights the molecular and functional consequences of IF-associated diseases (IF-pathies). Exciting challenges and opportunities face the IF field, including developing both a better understanding of the pathogenesis of IF-pathies and targeted therapeutic approaches.

Figure 1. The broad and complex distribution of IFs in human tissues.

The six types of IFs (types I–VI) are shown. To simplify the schematic, not all epithelial and nonepithelial tissues are displayed. Different keratin pairs are found primarily in unique epithelial cell types in a differentiation state–selective and/or cell type–specific distribution (e.g., K4/K13 in the esophagus, K20 in suprabasal but not in basal crypt enterocytes). The complexity of IF expression in tissues is exemplified in the intestine, in which epithelial cells express different compliments of simple epithelial keratins, the vasculature and other resident mesenchymal cells express vimentin, the smooth muscle layer expresses desmin, and neural elements of the enteric nervous system express neurofilaments. Numbers in parentheses indicate the type of IF. Bfsp1, beaded filament structural protein 1 (previously known as CP115 and filensin); Bfsp2 was previously known as CP49 and phakinin. NFH, high-molecular-weight neurofilament subunit; NFL, low-molecular-weight neurofilament subunit; NFM, middle-molecular-weight neurofilament subunit. This figure was adapted from Trends in cell biology (34).

Figure 2. IFs and human disease.

The involvement of IFs with human disease occurs at several levels. First, mutations in genes encoding IF proteins may either precipitate or predispose to a wide range of human diseases. It is also possible that natural selection has favored unique variants that may serve a protective role (16), although this hypothesis remains to be tested. Second, IF proteins, as a group, are essential for the formation of a variety of cell-specific inclusions that represent hallmarks of various diseases. Formation of these inclusions is generally independent of the presence of an IF mutation but does occur in the context of GFAP mutation in Alexander disease (18). Third, antibodies specific for IF proteins are routinely used in pathology laboratories across the world to help identify the origin of poorly differentiated tumors and are beginning to be used to assess tissue injury (directly in tissues, in blood, or in cerebrospinal fluid [CSF]) (16, 18). In addition, antibodies specific for IF proteins have been observed in the context of some autoimmune disease (16). ALS, amyotrophic lateral sclerosis; NIFID, neuronal IF inclusion disease.