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: 7172954
• 负责人: DAVID PATTERSON
• 金额: $ 23.01万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172954
• 关键词: 22q13; Accounting; Affect; Affective; Alleles; Anabolism; Autistic Disorder; Behavioral; Biochemical; Biochemistry; Biological Preservation; Breeding; Cells; Chinese Hamster; Chinese Hamster Ovary Cell; Chromosome Mapping; Chromosomes, Human, Pair 22; Clinical; Cognitive; Communication; Data; Development; Developmental Delay Disorders; Disease; Echolalia; Enzymes; Family; Gene Targeting; Genes; Genetic; Genomics; Goals; Health Care Costs; Human; Individual; Knockout Mice; Knowledge; Language; Language Disorders; Lead; Location; Lyase; Lyase Gene; Mental Retardation; Mental deficiency; Mus; Mutagenesis; Mutation; Nature; Ovary; Pathogenesis; Patients; Persons; Phenotype; Physiological; Protocols documentation; Purines; Purpose; Range; Reporting; Ritual compulsion; Series; Services; Susceptibility Gene; Syndrome; Talents; Technology; Testing; Thinking; Transgenes; Transgenic Mice; Transgenic Organisms; United States; adenylosuccinate lyase; early childhood; genetic analysis; insight; interest; mouse model; mutant; novel therapeutics; purine; purine metabolism; research study; social

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）： 腺苷酸琥珀酸裂解酶（ADSL）催化嘌呤从头生物合成的两个步骤。1984年，一种遗传综合征被描述，其中ADSL的缺乏导致严重的发育迟缓，在高达30%的病例中，自闭症特征（5）。目前，已知ADSL中有超过30种突变会导致ADSL缺陷。这些个体的临床表现可能差异很大。有趣的是，在2000年，据报道，一名ADSL缺陷患者具有最小的发育迟缓和自闭症特征。(6)1987年，我们将ADSL基因定位于人类染色体22（29）。ADSL基因的精确位置现在已知是在22 q13区域。这一区域的染色体异常也与自闭症有关。这些数据表明，ADSL缺乏症是自闭症以及精神发育迟滞和精神发育迟滞的一个促成因素。自闭症影响大约1在2000个人。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，偶尔具有上级但狭窄的天赋。可能存在固执、具体、情感迟钝和缺乏对他人思想的洞察力。我们已经分离和广泛的特点，中国仓鼠卵巢细胞（CHO-K1）细胞突变体，阿德尔，完全缺乏ADSL活动。我们现在建议创建和表征ADSL缺陷的小鼠模型。为此，我们将通过定点突变的方法对小鼠ADSL基因进行克隆。然后，我们将野生型和选择的突变型人ADSL基因导入不同系的转基因小鼠中，并通过适当的繁殖产生仅携带野生型或突变型人ADSL的小鼠。我们将生产具有R426 H突变的小鼠，该突变导致严重的发育迟缓，通常具有自闭症特征，以及导致轻度疾病的R303 C突变。然后，这些小鼠将进行神经解剖学，生物化学，生理学和行为学分析，以了解ADSL突变的后果。然后，我们将尝试用适当的药理学药物进行干预，以逆转ADSL缺乏症的影响，我们希望，其他形式的自闭症。

项目成果

Molecular characterization of the AdeI mutant of Chinese hamster ovary cells: a cellular model of adenylosuccinate lyase deficiency.

• DOI: 10.1016/j.ymgme.2010.08.022
• 发表时间: 2011-01
• 期刊: MOLECULAR GENETICS AND METABOLISM
• 影响因子: 3.8
• 作者: Vliet, Lydia K.;Wilkinson, Terry G., II;Duval, Nathan;Vacano, Guido;Graham, Christine;Zikanova, Marie;Skopova, Vaclava;Baresova, Veronika;Hnizda, Ales;Kmoch, Stanislav;Patterson, David
• 通讯作者: Patterson, David