Genetic Control of RNA metabolism: analysis of the SMARD1 helicase

描述（由申请人提供）：脊髓性肌萎缩伴1型呼吸窘迫（SMARD1）是一种人类运动神经元退行性疾病，由免疫球蛋白u结合蛋白2 （IGHMBP2）的功能丧失突变引起，这是一种假定的RNA/DNA解旋酶。合作研究者Cox先前通过定位克隆方法确定小鼠Ighmbp2基因是小鼠神经肌肉变性（nmd）表型的致病基因。我们还确定了其表型表达的主要遗传修饰因子（Mnm）。IGHMBP2的功能及其在SMARD1发病机制下的运动神经元变性中的作用尚不清楚。

DESCRIPTION (provided by applicant): Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a human motor neuron degenerative disease caused by loss-of-function mutations of the immunoglobulin u-binding protein 2 (IGHMBP2), a putative RNA/DNA helicase. The co-investigator Cox previously identified the mouse Ighmbp2 gene as the causative gene of the mouse neuromuscular degeneration (nmd) phenotype by a positional cloning approach. We have also identified a major genetic modifier of its phenotypic expression (Mnm). The function of IGHMBP2 and its role in the motor neuron degeneration that underlies the pathogenesis of SMARD1 are unknown. We propose to investigate the function of IGHMBP2 and to uncover the molecular defect(s) responsible for motor neuron degeneration caused by reduced IGHMBP2 levels, by implementing an inter-disciplinary and inter-institutional collaborative approach that will allow us to combine state of the art biochemical and genetic investigations. Toward this goal, we have isolated IGHMBP2 interacting proteins and small RNAs that associate with this helicase and we have employed powerful genetic approaches to identify the critical cell-types that require nmd gene activity using tissue-specific transgenic rescue. Our ability to manipulate the severity of the disease phenotype genetically with at least one modifier gene suggests that a molecular pathway exists with the potential for genetic or clinical intervention. Thus, the nmd mouse and the Mnm modifier gene provide a unique opportunity to identify the underlying processes of neurodegeneration and provide possible entry points in which to intervene in the disease pathway. Our genetic studies will be complemented by biochemical studies aimed towards characterization of the function of IGHMBP2 in cellular and mouse models of SMARD1 and we will extend our studies in human tissues from SMARD1 patients. These studies will likely uncover an entirely novel pathway of RNA regulation and will advance significantly our understanding of RNA processing in motor neurons and the contribution of RNA dysregulation in motor neuron degeneration.We propose to investigate the pathobiology of an inherited, human neurodegenerative disease. Our studies will shed light on pathogenetic mechanisms of human motor neuron diseases and promote the design of strategies to combat these lethal diseases.