THE GENETIC & FUNCTIONAL ANATOMICAL BASIS OF HGPPS

描述(申请人提供)：这项建议的目标是了解常染色体隐性遗传性水平凝视麻痹伴进行性脊柱侧弯(HGPPS；OMIM 607313)的遗传和功能解剖学基础，我们最近将其疾病基因定位在11q23-25。这种情况的特点是出生时完全没有共轭水平眼球运动，并在婴儿期和儿童期延迟发展为进行性脊柱侧弯。缺乏水平凝视很可能是外展神经核发育不良的结果，涉及外展神经运动神经元和中间神经元。招募更多的HGPPS患者使得在六个不同种族的近亲繁殖家庭中的候选区域得以确认和缩小。继续努力识别新患者可能会进一步缩小这一区域。这一建议的具体目的是：1)检验HGPPS基因是一个新的模式基因的假设。候选基因测序已经在进行中，将根据神经元表达模式、在神经发育中的假定功能以及小鼠和其他生物中的同源基因进行优先排序。2)验证外展神经核发育不良是HGPPS的解剖学基础的假说。创新的高分辨率常规、扩散张量和功能磁共振研究将在正常和具有遗传特征的患者中进行，以确定水平凝视功能障碍定位于脑干的功能解剖学基础，该功能解剖学尚未得到很好的可视化。3)验证HGPPS基因在外展神经核和其他脑干结构的正常发育中起重要作用的假设。我们将检测HGPPS基因在人类和小鼠胚胎脑组织(野生型和发育突变体)中的表达，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。我们开发的神经成像技术将适用于其他在眼动控制中重要的脑干结构的研究。了解HGPPS的解剖学和分子基础将有助于深入了解脑干中水平凝视中心和其他颅核的遗传程序化神经发育。

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.