Marie Unna遗传性稀毛症（MUHH）是一种常染色体显性遗传的先天性脱发，申请人所在课题组首次发现HR基因5’UTR区第二个上游开放读码框（uORF）U2HR突变可导致MUHH，但其具体分子生物学机制仍未阐明。项目前期发现U2HR在生理情况下具有可翻译性，且其对HR基因表达抑制的调控功能依赖其编码的氨基酸序列。我们推测U2HR可能通过核糖体阻滞机制行使对HR基因的表达抑制，其作用基础为U2HR编码的序列特异性小肽与核糖体蛋白之间的直接或间接相互作用，HR基因5’UTR中同时存在其他顺式元件协同作用，且阻滞效果受体内环境的精细调控。U2HR突变导致核糖体阻滞作用的丧失或减少，引起HR基因表达水平异常增高，导致MUHH。本项目将通过系列分子生物学实验验证以上假设，证明U2HR具有核糖体阻滞作用，发现协同U2HR调控的关键分子、蛋白和影响因素，揭示U2HR突变导致MUHH的分子生物学机制。

Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant inherited hair disorder characterized by congenital alopecia. Our group first identified loss-of-function mutations of the second upstream open reading frame (termed U2HR) in the 5’UTR of the human HR gene cause MUHH, but the specific molecular mechanism remains unclear. We previously found U2HR could be potentially translated, and its inhibitory function on HR expression relies on the specific amino acids of its encoded small peptide. We speculated that the specific nascent peptide encoded by U2HR, either alone or in cooperation with co-factors, could interact with components of the ribosomal tunnel to regulate translation and inducing ribosome stalling, thus negatively regulate HR protein translation efficiency. Other cis-acting elements may be existed and cooperate with uORFs in 5’UTR of the HR gene, and U2HR-mediated translational control can be fine-tuned under different stress conditions. Mutations in U2HR could therefore result in aberrant HR protein levels by loss or weaken the ability of stalling ribosome and subsequently result in MUHH. The aims of the present study are to testify the above hypothesis through a series of molecular biological experiments, to provide the evidence of ribosome stalling by U2HR, to find the key cofactor and influence factors of U2HR regulation, to elucidate the specific molecular mechanism underlying U2HR mutation resulted MUHH.