THE GENETIC & FUNCTIONAL ANATOMICAL BASIS OF HGPPS

描述（由申请人提供）：本提案的目的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，我们最近将其疾病位点定位于11 q23 -25。 这种情况的特征是出生时完全没有共轭水平眼球运动，婴儿期和儿童期进行性脊柱侧凸的发育延迟。 缺乏水平凝视可能是由于外展神经核发育不良，涉及外展神经运动神经元和中间神经元。 招募额外的HGPPS患者，使确认以及缩小候选区域在6个种族不同的近交系。 继续努力识别新患者可能会进一步缩小该地区。 本研究的具体目的是：1）验证HGPPS基因是一个新的模式基因的假设。 已经在进行中的候选基因测序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中的正向基因进行优先排序。2)目的：验证展神经核发育不良是HGPPS的解剖学基础这一假说。 将在正常和遗传特征患者中进行创新的高分辨率常规、弥散张量和功能MRI研究，以确定定位于脑干的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)验证HGPPS基因在展神经核和其他脑干结构的正常发育中的重要性。 我们将研究人类和小鼠（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遗传编程信号通路级联中的作用。 我们开发的神经影像学技术将适用于研究其他脑干结构，这些结构在眼神经控制中很重要。 了解HGPPS的解剖学和分子基础将提供深入了解共轭水平凝视中心和脑干中其他颅核的遗传编程神经发育。

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.