Kindler syndrome is an autosomal recessive disorder characterized by skin
atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion
protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin
atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in
Kindler syndrome. We identified altered distribution of several basement membrane
proteins, including types IV, VII, and XVII
collagens and laminin-332 in
Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as beta1 and alpha6
integrins and
cytokeratin 15 was noted. At the cellular level, there was loss of
beta4 integrin immunolocalization and random distribution of laminin-332 in
Kindler syndrome keratinocytes. Of note, active
beta1 integrin was reduced but overexpression of fermitin family homolog-1 restored
integrin activation and partially rescued the
Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in
integrin activation and demonstrates that lack of this
protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of
Kindler syndrome.