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(申请人提供)：腺基琥珀酸裂解酶(ADSL)催化从头合成嘌呤的两步反应。1984年，描述了一种遗传综合征，ADSL的缺陷会导致严重的发育迟缓，在高达30%的病例中，会导致自闭症的特征。目前，已知有30多个ADSL基因突变导致ADSL缺陷。这些人的临床情况可能有很大的不同。有趣的是，2000年报道了一例ADSL缺乏症患者，具有最小的发育延迟和自闭症特征。(6)1987年，我们将ADSL基因定位于人类22号染色体(29)。目前已知ADSL基因的准确位置在22q13区域。该区域的染色体异常也与自闭症有关。这一数据表明，ADSL缺陷是自闭症的一个促成因素，也是精神运动迟缓和智力低下的一个因素。大约每2000人中就有1人患有自闭症。定义特征是社交能力、语言和交流能力受损，以及兴趣和活动的范围。智力缺陷可能存在，也可能不存在，认知特征也很狭窄，偶尔会有卓越但狭隘的天赋。坚持不懈、具体、情感迟钝、缺乏对他人想法的洞察力可能会出现。我们分离并鉴定了一个中国仓鼠卵巢细胞(CHO-K1)细胞突变体Adel，它完全缺乏ADSL活性。我们现在建议创建并表征ADSL缺陷的小鼠模型。为此，我们将通过定向突变使小鼠ADSL基因失活。然后，我们将把野生型和选定的突变型人类ADSL基因引入不同的转基因小鼠系中，并通过适当的育种创造出只携带野生型或突变型人类ADSL的小鼠。我们将培育出R426H突变和R303C突变的小鼠，R426H突变导致严重发育迟缓，通常具有自闭症特征，R303C突变导致轻度疾病。然后对这些小鼠进行神经解剖学、生化、生理学和行为学分析，以了解ADSL突变的后果。然后，我们将尝试用适当的药物进行干预，以逆转ADSL缺陷的影响，我们希望也能逆转其他形式的自闭症。