AUTISM AND AMPS LYASE MUTATIONS: CELL AND MOUSE MODELS

自闭症和 AMPS 裂解酶突变：细胞和小鼠模型

• 批准号: 6579811
• 负责人: DAVID PATTERSON
• 金额: $ 27.72万
• 依托单位: ELEANOR ROOSEVELT INST FOR CANCER RES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-11 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579811
• 关键词: adenosine monophosphate; amidine lyase; autism; clinical research; disease /disorder model; enzyme deficiency; gene mutation; genetic models; genetically modified animals; human genetic material tag; human subject; laboratory mouse; nucleotide metabolism; purine /pyrimidine metabolism disorder; succinates; tissue /cell culture

DESCRIPTION (provided by applicant): Adenylosuccinate lyase (ADSL) catalyzes two steps of de novo purine biosynthesis. In 1984, a genetic syndrome was described in which a deficiency in ADSL leads to profound developmental delay and, in up to 30% of cases, autistic features (5). Currently, over 30 mutations in ADSL are known to cause ADSL deficiency. The clinical picture in these individuals can vary widely. Interestingly, in 2000 an ADSL deficiency patient was reported with minimal developmental delay and autistic features. (6) In 1987, we mapped the gene for ADSL to human chromosome 22 (29). The precise location of the ADSL gene is now known to be in the 22q13 region. Chromosomal anomalies in this region are also associated with autism. This data suggests that ADSL deficiency is a contributing factor to autism as well as to psychomotor delay and mental retardation. Autism affects approximately 1 in 2000 individuals. Defining features are impaired sociability, language and communication, and range of interests and activities. Mental deficiency may or may not be present, and the cognitive profile is narrow, occasionally with superior but narrow talent. Perseveration, concreteness, affective blunting, and lack of insight into other persons' thinking may be present. We have isolated and extensively characterized a Chinese hamster ovary cell (CHO-K1) cell mutant, Adel, completely lacking in ADSL activity. We now propose to create and characterize a mouse model of ADSL deficiency. For this purpose, we will inactivate the mouse ADSL gene by targeted mutagenesis. We will then introduce the wild type and selected mutant human ADSL genes into different lines of transgenic mice and by appropriate breeding create mice carrying only the wild type or mutant forms of human ADSL. We will produce mice with the R426H mutation that leads to severe developmental delay, often with autistic features, and the R303C mutation that leads to mild disease. These mice will then be analyzed neuroanatomically, biochemically, physiologically, and behaviorally to understand the consequences of ADSL mutations. We will then attempt to intervene with appropriate pharmacological agents to reverse the effects of ADSL deficiency, and, we hope, to other forms of autism.

描述（由申请人提供）：腺苷糖酸酯裂解酶（ADSL）催化了从头嘌呤生物合成的两个步骤。 1984年，描述了一种遗传综合征，其中ADSL缺乏导致深远的发育延迟，并且在30％的病例中，自闭症特征（5）。当前，已知已知30多个ADSL突变会导致ADSL缺乏。这些人中的临床情况可能会有所不同。有趣的是，在2000年，据报道，一名ADSL缺乏症患者的发育延迟和自闭症特征最少。 （6）1987年，我们将ADSL的基因映射到人类染色体22（29）。现在已知ADSL基因的确切位置位于22q13地区。该区域的染色体异常也与自闭症有关。该数据表明，ADSL缺乏症是导致自闭症以及精神运动延迟和智力低下的因素。自闭症影响2000人中约有1个。定义特征是社交，语言和沟通以及兴趣和活动范围的障碍。精神缺乏可能存在，也可能不存在，认知能力狭窄，偶尔具有优越但狭窄的才能。可能存在毅力，具体性，情感钝化以及对他人思想的缺乏见解。我们已经孤立并广泛地表征了中国仓鼠卵巢细胞（CHO-K1）细胞突变体Adel，完全缺乏ADSL活性。现在，我们建议创建和表征ADSL缺乏症的鼠标模型。为此，我们将通过靶向诱变使小鼠ADSL基因失活。然后，我们将将野生型和选择的突变体ADSL基因引入不同的转基因小鼠，并通过适当的繁殖产生仅带有人类ADSL的野生型或突变形式的小鼠。我们将产生带有R426H突变的小鼠，从而导致严重的发育延迟，通常具有自闭症特征，以及导致轻度疾病的R303C突变。然后，这些小鼠将通过生化，生理和行为上的神经解剖学进行分析，以了解ADSL突变的后果。然后，我们将尝试与适当的药理学剂进行干预，以扭转ADSL缺乏症的影响，并希望将其转化为其他形式的自闭症。