Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

Joey E. Lai-Cheong^*, Maddy Parsons, Akio Tanaka^*, Siegfried Ussar, Andrew P. South, Sethuraman Gomathy^¶, John B. Mee^*, Jean-Baptiste Barbaroux^*, Tanasit Techanukul^*, Noor Almaani^*, Suzanne E. Clements^*, Ian R. Hart^|| and John A. McGrath^*

From the St John’s Institute of Dermatology^* and Randall Division of Cell and Molecular Biophysics, King’s College London, London, United Kingdom; the Department of Molecular Medicine, Max-Planck Institute, Martinsried, Germany; the Division of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland; the Department of Dermatology,^¶ All India Institute of Medical Sciences, New Delhi, India; and the Institute of Cancer,|| Bart’s and The London Schools of Medicine, London, United Kingdom

Kindler syndrome is an autosomal recessive disorder characterizedby skin atrophy and blistering. It results from loss-of-functionmutations in the FERMT1 gene encoding the focal adhesion protein,fermitin family homolog-1. How and why deficiency of fermitinfamily homolog-1 results in skin atrophy and blistering areunclear. In this study, we investigated the epidermal basementmembrane and keratinocyte biology abnormalities in Kindler syndrome.We identified altered distribution of several basement membraneproteins, including types IV, VII, and XVII collagens and laminin-332in Kindler syndrome skin. In addition, reduced immunolabelingintensity of epidermal cell markers such as β1 and ${alpha}$ 6 integrinsand cytokeratin 15 was noted. At the cellular level, there wasloss of β4 integrin immunolocalization and random distributionof laminin-332 in Kindler syndrome keratinocytes. Of note, activeβ1 integrin was reduced but overexpression of fermitinfamily homolog-1 restored integrin activation and partiallyrescued the Kindler syndrome cellular phenotype. This studyprovides evidence that fermitin family homolog-1 is implicatedin integrin activation and demonstrates that lack of this proteinleads to pathological changes beyond focal adhesions, with disruptionof several hemidesmosomal components and reduced expressionof keratinocyte stem cell markers. These findings collectivelyprovide novel data on the role of fermitin family homolog-1in skin and further insight into the pathophysiology of Kindlersyndrome.