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异性屏障渗透性缺陷（常染色体隐性遗传性先天性鱼鳞病; ARCI）的新型突变基因，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遗传学的最新进展说明了遗传策略对于研究新认识的代谢途径和正常皮肤屏障功能机制的作用。平行的生化研究阐明了这些发现的重要功能方面。迄今为止，位置克隆，特别是在大的血缘关系的家庭纯合性定位，一直是一个有效的策略，以解开基因突变和不同的遗传形式的鱼鳞病之间的关系。DNA测序技术的最新发展使得快速且相对便宜地分析个体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，我们建议通过结合基因分型和下一代测序（NGS）将这些新技术应用于我们队列中剩余的未分类患者。为了鉴定新的突变的ARCI基因并确定它们在表皮脂质途径中的功能和相互作用，我们将：1。使用现代基因分型和测序技术对大型ARCI患者和家族进行遗传分析。2.分析相应的基因产物及其在表皮脂质通路中的功能。实现这些目标将需要与皮肤脂质生物学领域的专家进行补充合作，他们将提供新型ARCI蛋白的生化表征。该项目的结果将加速对ARCI基因在皮肤屏障中作用的理解，并将为皮肤疾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.