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

该项目旨在发现导致皮肤特定屏障通透性缺陷的新突变基因(常染色体隐性遗传性先天性鱼鳞病；ARCI)，以及这些基因产物如何在表皮脂质途径中发挥作用和相互作用。ARCI遗传学的最新进展表明，遗传策略对于研究新发现的代谢途径和正常皮肤屏障功能的机制具有强大的作用。平行的生化研究阐明了这些发现的重要功能方面。到目前为止，位置克隆，特别是在大型血缘家庭中的纯合性定位，一直是揭示基因突变与鱼鳞病不同遗传形式之间关系的有效策略。DNA测序技术的最新发展使快速和相对廉价地分析一个人的整个外显子组成为可能，即使在遗传信息较少的家庭中也是如此。在本项目中，我们建议通过将基因分型和下一代测序(NGS)相结合，将这些新技术应用于我们队列中剩余的未分类患者。为了鉴定新突变的ARCI基因，并确定它们在表皮脂质通路中的功能和相互作用，我们将：1.利用现代基因分型和测序技术对大量ARCI患者和家系进行基因分析。2.分析表皮脂质途径中相应的基因产物及其功能。实现这些目标需要皮肤脂质生物学领域的专家的补充合作，他们将提供新的ARCI蛋白的生化特征。该项目的结果将加速了解ARCI基因在皮肤屏障中的作用，并将为皮肤病的治疗提供新的靶点和策略。

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.