Rare Diseases Symptoms Automatic Extraction

Loss-of-function FERMT1 mutations in kindler syndrome implicate a role for fermitin family homolog-1 in integrin activation.

[kindler syndrome]

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.

Diseases presenting "loss-of-function mutations" symptom

  • achondroplasia
  • alpha-thalassemia
  • aromatase deficiency
  • child syndrome
  • cowden syndrome
  • dystrophic epidermolysis bullosa
  • epidermolysis bullosa simplex
  • erythropoietic protoporphyria
  • esophageal adenocarcinoma
  • familial hypocalciuric hypercalcemia
  • harlequin ichthyosis
  • hirschsprung disease
  • kallmann syndrome
  • kindler syndrome
  • lamellar ichthyosis
  • neonatal adrenoleukodystrophy
  • pendred syndrome
  • werner syndrome
  • x-linked adrenoleukodystrophy

This symptom has already been validated