GENETICS OF JUVENILE AMYOTROPHIC LATERAL SCLEROSIS (JALS)

青少年肌萎缩侧索硬化症 (JALS) 的遗传学

• 批准号: 6217885
• 负责人: Phillip Frazier CHANCE
• 金额: $ 26.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217885
• 关键词: amyotrophic lateral sclerosis; autosomal dominant trait; cell line; clinical research; family genetics; gene expression; genetically modified animals; human genetic material tag; human puberty; human subject; immunologic assay /test; in situ hybridization; laboratory mouse; linkage mapping; molecular cloning; molecular pathology; neurogenetics; nucleic acid sequence; polymerase chain reaction

Chronic Juvenile Amyotrophic Lateral Sclerosis (JALS) combines the features of a spinal muscular atrophy syndrome with upper motor neuron dysfunction. We have identified a large pedigree in Southern Maryland segregating an autosomal dominant gene for this form of JALS. Over 75 persons in this family are affected with a peripheral neuropathy characterized by an age of onset in adolescence with slow progression, leading to severe neuromuscular impairment by the fourth and fifth decades. Altered or abnormal expression of a motor neuron-specific component or a more widely-expressed protein whose function is crucial to motor neuron function is suspected. The gene for this disorder does not map to known regions of other motor neuron syndromes including the Familial Amyotrophic Lateral Sclerosis (ALS1) locus on chromosome 21, the Juvenile Amyotrophic Lateral Sclerosis (ALS2) locus on chromosome 2 or to the Spinal Muscle Atrophy (SMA) locus on chromosome 5. We propose to investigate the molecular basis of the JALS gene in this pedigree by techniques of positional cloning, including linkage analysis, physical map construction and analysis of transcripts and candidate genes. Experiments aimed to characterize the patterns and distribution of expression of this gene at the transcriptional and protein revels are proposed through in situ hybridization analysis, construction of transgenic animals, protein/antibody production and analysis in a motor neuron cell culture system. Genetic analysis in this large JALS pedigree affords the opportunity to identify and characterize an important motor neuron component.

慢性青少年肌萎缩侧索硬化症 (JALS) 结合了 伴上运动神经元的脊髓性肌萎缩综合征的特征 功能障碍。我们在马里兰州南部发现了一个大的血统 分离出这种形式的 JALS 的常染色体显性基因。 75岁以上 这个家庭中的人患有周围神经病 其特点是发病年龄为青春期且进展缓慢， 导致第四和第五次严重的神经肌肉损伤 几十年。运动神经元特异性表达改变或异常 其功能至关重要的成分或更广泛表达的蛋白质 怀疑运动神经元功能。这种疾病的基因确实 未映射到其他运动神经元综合征的已知区域，包括 家族性肌萎缩侧索硬化症 (ALS1) 基因座位于 21 号染色体上， 2 号染色体上的青少年肌萎缩侧索硬化症 (ALS2) 基因座 或 5 号染色体上的脊髓肌萎缩 (SMA) 基因座。我们建议 研究该家系中 JALS 基因的分子基础 定位克隆技术，包括连锁分析、物理克隆 转录本和候选基因的图谱构建和分析。 实验旨在表征的模式和分布 该基因在转录和蛋白质水平上的表达是 通过原位杂交分析提出，构建 转基因动物、电机中的蛋白质/抗体生产和分析 神经元细胞培养系统。 JALS 大型血统的遗传分析 提供了识别和表征重要电机的机会 神经元成分。