THE GENETIC & FUNCTIONAL ANATOMICAL BASIS OF HGPPS

遗传因素

• 批准号: 6932303
• 负责人: JOANNA C JEN
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932303
• 关键词: biological signal transduction; brain mapping; brain stem; clinical research; congenital disorders; cranial nerves; developmental genetics; eye movement disorders; eye movements; family genetics; functional magnetic resonance imaging; gene expression; genetic disorder; genetic mapping; genotype; human fetus tissue; human subject; in situ hybridization; laboratory mouse; magnetic resonance imaging; neuroanatomy; neurogenesis; neurophysiology; nucleic acid sequence; patient oriented research; scoliosis

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the genetic and functional anatomical basis underlying autosomal recessive horizontal gaze palsy with progressive scoliosis (HGPPS; OMIM 607313), the disease locus of which we recently mapped to 11q23-25. This condition is characterized by a complete absence of conjugate horizontal eye movement at birth, with a delayed development of progressive scoliosis during infancy and childhood. Absent horizontal gaze likely results from maldevelopment of the abducens nuclei, involving both abducens moto- and inter-neurons. The recruitment of additional HGPPS patients has enabled the confirmation as well as narrowing of the candidate region in six ethnically diverse inbred families. Continuing effort to identify new patients may further narrow the region. The specific aims for this proposal are: 1) To test the hypothesis that the HGPPS gene is a novel patterning gene. Already underway, candidate gene sequencing will be prioritized based on neuronal expression pattern, putative function in neurodevelopment, and orthologous genes in mice and other organisms. 2) To test the hypothesis that maldevelopment of the abducens nucleus is the anatomical basis of HGPPS. Innovative high-resolution conventional, diffusion tensor, and functional MRI studies will be performed in normal and genetically characterized patients to define the functional anatomical basis of horizontal gaze dysfunction localizing to the brainstem, which has not been well visualized. 3) To test the hypothesis that the HGPPS gene is important in the normal development of the abducens nucleus and other brainstem structures. We will examine expression of the HGPPS gene in embryonic brain tissue from human and mouse (wildtype and developmental mutants) to study its role in the cascade of genetically programmed signaling pathways mediating neurogenesis. Neuroimaging techniques that we develop will be applicable to the study of other brainstem structures important in oculomotor control. Understanding the anatomical and molecular basis of HGPPS will provide insight into the genetically programmed neurodevelopment of the conjugate horizontal gaze center and other cranial nuclei in the brainstem.

描述（由申请人提供）：本提案的目标是了解常染色体隐性水平凝视麻痹伴进行性脊柱侧凸（HGPPS；OMIM 607313）的遗传和功能解剖学基础，我们最近将其疾病基因座映射到 11q23-25。 这种情况的特点是出生时完全缺乏共轭水平眼球运动，并且在婴儿期和儿童期延迟发展进行性脊柱侧弯。 缺乏水平凝视可能是由于外展神经核发育不良造成的，涉及外展运动神经元和间神经元。 招募额外的 HGPPS 患者已确认并缩小了六个不同种族近交家族的候选区域。 继续努力识别新患者可能会进一步缩小区域范围。 该提案的具体目标是：1）检验HGPPS基因是一种新型模式基因的假设。 候选基因测序已经在进行中，将根据神经元表达模式、神经发育中的推定功能以及小鼠和其他生物体的直系同源基因确定优先顺序。 2) 检验外展核发育不良是 HGPPS 解剖学基础的假设。 创新的高分辨率常规、扩散张量和功能性 MRI 研究将在正常和具有遗传特征的患者中进行，以确定脑干水平凝视功能障碍的功能解剖学基础，这一点尚未得到很好的可视化。 3) 检验HGPPS基因对于外展核和其他脑干结构的正常发育很重要的假设。 我们将检测人类和小鼠（野生型和发育突变体）胚胎脑组织中 HGPPS 基因的表达，以研究其在介导神经发生的基因编程信号通路级联中的作用。 我们开发的神经成像技术将适用于对动眼神经控制重要的其他脑干结构的研究。 了解 HGPPS 的解剖学和分子基础将有助于深入了解共轭水平凝视中心和脑干中其他颅核的基因编程神经发育。