A04 Characterization of genes in renal-skin syndromes



  • B01
    • Walz
    • Kammerer
  • B02
    • Köttgen
  • B04
    • Bergmann
  • B06
    • Lausch
    • Schmidts
  • B07
    • Lienkamp
    • Arnold



  • Z01
    • Nitschke
    • Eimer
  • Z02
    • Brox
    • Ronneberger
Cristina Has

Cristina Has

Principal investigator of

We have recently identified a novel hereditary disease linking junctional Epidermolysis Bullosa (ILNEB) to congenital nephrotic syndrome. The underlying mutations were found in the gene for integrin α3 (ITGA3), which is known to mediate cell-matrix interactions in the skin and glomerular podocytes. We therefore hypothesize that mutations in a subset of shared skin and glomerular genes, predominantly encoding for adhesion and matrix proteins, cause renal-skin syndromes that may be currently under-diagnosed. The major goal of this proposal is to identify these genes, and to define the underlying unifying molecular mechanisms that lead to renal and skin abnormalities. Towards this goal, we want to establish in vitro and in vivo model systems that can be used to validate putative disease genes and define the molecular defects caused by their mutations. The zebrafish embryo is readily accessible for time-lapse imaging and genetic manipulation. Since the epithelial cell-matrix interactions are evolutionary highly conserved, the zebrafish represents an ideal model to study itga3 and other cell-matrix paralogs. We propose therefore to combine gene identification and the characterization of gene mutations with a functional analysis in zebrafish embryos. In addition, we will use in vitro systems of human keratinocytes from patients to elucidate the principle disease mechanism(s) that link epidermolysis to proteinuria. Specifically, we aim to: 1) establish genotype-phenotype correlations for the recently discovered renal-skin syndrome, utilizing the keratinocyte and zebrafish model, 2) perform proteomics of extracellular matrix and focal adhesions in kidney and skin to dissect molecular mechanisms affected by the genetic mutations, and 3) identify and characterize additional genes causing renal-skin syndromes in patients not linked to ITGA3 mutations. Collectively, these data should contribute to an in-depth understanding of the mechanisms underlying hereditary syndromes associated with skin and renal abnormalities.