Molecular characterization and functional analysis of novel ARCI genes involved in differentiation of human epidermis

• Applicant: Professorin Judith Fischer, Ph.D.
• Subject Area: Human Genetics
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258607292

This project addresses aims to discover novel mutated genes causing specific barrier permeability defects of the skin (autosomal recessive congenital ichthyoses; ARCI) and how do these gene products function and interact within the epidermal lipid pathways. Recent progress in the genetics of ARCI has illustrated the power of genetic strategies for the investigation of newly recognized metabolic pathways and for the mechanisms of barrier function in normal skin. Parallel biochemical studies have elucidated important functional aspects of these findings. Until now, positional cloning, especially homozygosity mapping in large consanguineous families, has been an effective strategy to unravel the relationships between gene mutations and the different genetic forms of ichthyoses. Recent developments in DNA sequencing technologies have made it possible to analyze rapidly and relatively inexpensively the whole Exome of an individual, even in genetically less informative families. In the present project, we propose to apply these new technologies, by combining genotyping and next-generation sequencing (NGS), to the remaining unclassified patients of our cohort. To identify novel mutated ARCI genes and determine their function and interactions within the epidermal lipid pathways we will:1. Perform genetic analyses of a large cohort of ARCI patients and families with modern genotyping and sequencing technologies. 2. Analyze the corresponding gene products and their function within the epidermal lipid pathways.Achieving these goals will require supplementary collaborations with experts in the field of skin lipid biology who will provide biochemical characterization of novel ARCI proteins. The results of this project will accelerate the understanding of the role of ARCI genes in the skin barrier, and will deliver novel targets and strategies for the therapy of skin disorders.

• DFG Programme: Research Grants