ANGELMAN SYNDROME, GENOMIC IMPRINTING AND GABA RECEPTOR

15号染色体近端长臂的缺失在 大多数患有两种不同遗传性疾病的患者，安杰曼综合征 (AS)和Prader-Willi综合征(PWS)。这两个综合征中的缺失， 在细胞遗传学和分子生物学上的定义，在程度上相似但不同 父母出身的。AS中的缺失发生在母系遗传的 染色体的缺失，而PWS中的缺失完全来自父亲。 在几个非缺失的PWS病例中，单亲母体二体 检测到。单亲父系二体现在已经在非缺失中被观察到 作为案例。这些发现有力地表明，在这种情况下，一个或多个基因 区域受到基因组印记的影响。编码GABAA的基因 (tau-氨基丁酸)受体β3亚基已定位于 AS/PWS次区域。更多的图谱数据表明GABAA受体 β3亚基基因可从缺失的临界区中排除 PWS重叠，AS不重叠。从功能上讲，受体的缺陷 对于牛氨基丁酸，它是主要的抑制物 脊椎动物大脑中的神经递质，可以解释临床 AS的表现包括癫痫发作，手臂痉挛，严重 精神发育迟缓和无法控制的笑声。为了 调查这种神经递质受体的异常是否 AS患者非缺失型DNA与AS的发生发展相关 将对该基因的突变和重排进行筛查。抗体 为了研究GABAA受体β3亚基的上调 其在正常脑组织和正常脑组织中的表达。这样做的另一个主要目标是 建议调查GABAA受体Beta3亚单位基因是否 留下了印记。在将用于解决后者的方法中 目的是研究β3亚单位基因的甲基化模式。 父系和母系衍生的15号染色体，以及 父系和母系β3亚基等位基因的研究 在小鼠脑中差异表达。

Deletions of the proximal long arm of chromosome 15 are found in the majority of patients with two distinct genetic disorders, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). The deletions in the two syndromes, defined cytogenetically and molecularly, are similar in extent but differ in parental origin. Deletions in AS occur on the maternally-inherited chromosome, whereas deletions in PWS are exclusively of paternal origin. In several nondeletion cases of PWS, uniparental maternal disomy has been detected. Uniparental paternal disomy has now been observed in nondeletion AS cases. These findings strongly suggest that one or more genes in this region are subject to genomic imprinting. The gene encoding the GABAA (tau-aminobutyric acid) receptor beta3 subunit has been localized to the AS/PWS subregion. Additional mapping data indicate that the GABAA receptor beta3 subunit gene can be excluded from the critical region of deletion overlap of PWS but not that of AS. Functionally, a defect in a receptor for tau-aminobutyric acid, which is the principal inhibitory neurotransmitter in vertebrate brain, could account for the clinical manifestations of AS which include seizures, jerky arm movements, severe mental retardation and uncontrollable bouts of laughter. In order to investigate whether an abnormality in this neurotransmitter receptor is associated with the development of AS, the DNA of nondeletion AS patients will be screened for mutations and rearrangements of this gene. Antibodies to the GABAA receptor beta3 subunit will be raised in order to investigate its expression in normal and AS brain. The other main objective of this proposal is to investigate whether the GABAA receptor beta3 subunit gene is imprinted. Among the approaches that will be used to address the latter goal is the study of the methylation pattern of the beta3 subunit gene on the paternally- and maternally-derived chromosomes 15, and the investigation of whether the paternal and maternal beta3 subunit alleles are differentially expressed in mouse brain.