THE GENETIC & FUNCTIONAL ANATOMICAL BASIS OF HGPPS

遗传因素

• 批准号: 7460879
• 负责人: JOANNA C JEN
• 金额: $ 36.76万
• 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/7460879
• 关键词: 11q23; Accounting; Affect; Birth; Brain; Brain Stem; Candidate Disease Gene; Cell Nucleus; Cephalic; Child; Childhood; Clinical; Condition; Cranial Nerves; Defect; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Embryo; Embryonic Development; Eye Movements; Family; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Genetic Programming; Genetic Recombination; Genotype; Goals; Greek; Human; Impairment; In Situ Hybridization; Individual; Localized; Magnetic Resonance Imaging; Maps; Mediating; Microsatellite Repeats; Modeling; Molecular; Mus; Mutant Strains Mice; Nerve; Neurons; Online Mendelian Inheritance In Man; Organism; Orthologous Gene; Pathway interactions; Patients; Pattern; Personal Satisfaction; Phenotype; Recruitment Activity; Relative (related person); Resolution; Role; Scanning; Signal Pathway; Structure; Syndrome; Techniques; Testing; Weight; abducens nucleus; base; brain tissue; gaze palsy; genetic pedigree; horizontal gaze; human tissue; infancy; innovation; insight; mutant; neurodevelopment; neurogenesis; neuroimaging; novel; oculomotor; positional cloning; programs; relating to nervous system; scoliosis; tool; white matter

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）：该提案的目的是了解带有进行性脊柱侧弯的遗传和功能解剖基础基础常染色体隐性水平凝视麻痹（HGPPS； OMIM 607313），我们最近将其映射到11Q23-25。 这种疾病的特征是出生时完全没有水平眼运动，在婴儿期和儿童期间进行性脊柱侧弯的发展延迟。 缺乏水平凝视可能是由于外皮核的核心发展而导致的，涉及外皮的摩托元和神经元。 其他HGPPS患者的招募已使六个种族多元化的近交系列中的候选区域范围缩小。 继续努力识别新患者可能会进一步缩小该地区。 该提案的具体目的是：1）检验HGPPS基因是一种新型图案基因的假设。 已经在进行的情况下，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的直系同源基因确定候选基因测序。 2）检验假设，即外星人核的马尔德开发是HGPP的解剖基础。 创新的高分辨率常规，扩散张量和功能性MRI研究将在正常和遗传表征的患者中进行，以定义位于脑干上的水平凝视功能障碍的功能解剖基础，这尚未得到很好的可视化。 3）测试假说，即HGPPS基因在外皮核和其他脑干结构的正常发育中很重要。 我们将研究HGPPS基因在人和小鼠（WildType和发育突变体）中的胚胎脑组织中的表达，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。 我们开发的神经影像学技术将适用于对动眼控制重要的其他脑干结构的研究。 了解HGPP的解剖学和分子基础将提供有关脑干中共轭水平凝视中心和其他颅核的遗传编程神经发育的洞察力。