Three related classic cell biology papers, published in 1991, had a huge positive impact on the field of cell biology and far beyond. Two of these papers elegantly showed that mutations in keratin 14 (Coulombe et al., cited >480 times; Bonifas et al., cited >320 times) cause the blistering skin disease epidermolysis bullosa simplex (EBS). Prior to this, the function of the >70 intermediate filament proteins was poorly understood. Furthermore, no direct disease connection was known for any intermediate filament protein, except for that published in the earlier 1991 paper (Vassar et al.), which found a blistering skin phenotype (similar to human EBS) in transgenic mice expressing keratin 14 with a carboxy-terminal deletion. This was the impetus for Pierre Coulombe (at the Fuchs laboratory) to search for keratin mutations in patients; the Bonifas study was based on classic genetic linkage analysis. Another major implication of these studies was the elucidation of mechanical cytoprotection as an important function of keratins and other intermediate filament proteins.

mutations in intermediate filament genes cause or predispose to >70 distinct human skin, cardiac, neuronal, liver, premature ageing, ocular and metabolic diseases

The success of using the keratin 14 transgenic mice led us to show in 1995 that the expression of a keratin 18 point mutation in mice, which is identical to the keratin 14 mutation in EBS patients, causes profound predisposition to liver injury, which we then validated in human studies. We further showed that keratin functions extend to non-mechanical roles. Similarly, other laboratories generated mouse models or examined humans directly, to show that mutations in intermediate filament genes cause or predispose to >70 distinct human skin, cardiac, neuronal, liver, premature ageing, ocular and metabolic diseases.

So what is next? Cell biology helped to unfold the causes of a range of human diseases, but now we need to circle back to the bench to develop cures for the broad array of intermediate filament-related diseases known as IF-pathies.