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）：腺苷琥珀酸裂解酶（ADSL）催化嘌呤从头生物合成的两个步骤。 1984 年，描述了一种遗传综合症，其中 ADSL 缺陷会导致严重的发育迟缓，并且在高达 30% 的病例中会出现自闭症特征 (5)。目前，已知超过 30 种 ADSL 突变会导致 ADSL 缺陷。这些个体的临床表现可能差异很大。有趣的是，2000 年，据报道一名 ADSL 缺陷患者的发育迟缓和自闭症特征极小。 (6) 1987年，我们将ADSL基因定位到人类22号染色体上(29)。目前已知ADSL基因的精确位置位于22q13区域。该区域的染色体异常也与自闭症有关。该数据表明，ADSL 缺陷是导致自闭症、精神运动迟缓和精神发育迟滞的一个因素。自闭症影响大约 2000 人中就有 1 人。定义特征是社交能力、语言和沟通能力以及兴趣和活动范围受损。智力缺陷可能存在，也可能不存在，认知范围狭窄，偶尔具有优越但狭窄的才能。可能会出现固执、具体、情感迟钝以及缺乏对他人想法的洞察力。我们分离并广泛表征了一种完全缺乏 ADSL 活性的中国仓鼠卵巢细胞 (CHO-K1) 细胞突变体 Adel。我们现在建议创建并表征 ADSL 缺陷的小鼠模型。为此，我们将通过定向诱变灭活小鼠 ADSL 基因。然后，我们将野生型和选定的突变型人类ADSL基因引入不同品系的转基因小鼠中，并通过适当的育种创建仅携带野生型或突变型人类ADSL的小鼠。我们将培育出带有 R426H 突变的小鼠，这种突变会导致严重的发育迟缓，通常具有自闭症特征，而 R303C 突变则会导致轻微的疾病。然后将对这些小鼠进行神经解剖学、生物化学、生理学和行为学分析，以了解 ADSL 突变的后果。然后，我们将尝试使用适当的药物进行干预，以扭转 ADSL 缺陷的影响，并希望扭转其他形式的自闭症的影响。