Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice.
Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice.
复制标题
小鼠中 A 型 γ-氨基丁酸受体的 γ 3、α 5 或 β 3 亚基缺失的表型后果。
DOI：
--
复制
发表时间：
1994
影响因子：
11.1
通讯作者：
E. Rinchik
中科院分区：
文献类型：
--
作者：
C. Culiat;Lisa Stubbs;Clyde S. Montgomery;Liane B. Russell;E. Rinchik;E. Rinchik
已知有三个基因(Gabrg3、Gabra5和GABRB3)分别编码A型γ-氨基丁酸受体的γ3、α5和β3亚单位，位于小鼠7号染色体的粉眼稀释区(P)附近。该区域与人类15号染色体的一个片段有同源性，该片段与Angelman综合征有关，后者是一种遗传性神经行为障碍。通过将gabrg3定位在一组p-座位缺失上，我们已经确定了该簇中基因的顺序是centromere-p(D15S12h)-Gabrg3-Gabra5-Gabrb3-telom ERE。与GABRB3一样，Gabra5和Gabrg3基因都不会在成年小鼠的大脑中留下功能印记。所有三个亚基缺失的小鼠出生时就会死于腭裂，尽管很少有幸存者(约5%)没有腭裂，但确实表现出神经异常，特征是震颤、步态颠簸和步态迟缓。我们先前已经提出，β3亚基的缺失可能是导致裂隙缺陷的原因。然而，最值得注意的是，在这份报告中，我们描述了携带两个重叠的、互补的p缺失的小鼠，这些小鼠无法表达Gamma 3转录本，以及来自另一个品系的既不表达Gamma 3转录本也不表达Alpha 5转录本的小鼠。令人惊讶的是，这两个品系的小鼠都是表型正常的，没有表现出任何罕见幸存者的神经症状，这些症状在所有三个亚基(伽马3、阿尔法5和贝塔3)都缺失了。因此，这些小鼠提供了一个完整的A型γ-氨基丁酸受体背景，它不存在任何通常包含伽马3和/或α5亚单位的受体亚型。缺乏Gamma 3和/或Alpha 5亚单位的小鼠缺乏明显的神经表型，这也表明这些基因的突变不太可能为人类的Angelman综合征提供有用的动物模型。
Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the gamma 3, alpha 5, and beta 3 subunits of the type A gamma-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) locus in mouse chromosome 7. This region shares homology with a segment of human chromosome 15 that is implicated in Angelman syndrome, an inherited neurobehavioral disorder. By mapping Gabrg3 on a panel of p-locus deletions, we have determined that the order of genes within this cluster is centromere-p(D15S12h)-Gabrg3-Gabra5-Gabrb3-telom ere. Like Gabrb3, neither the Gabra5 nor Gabrg3 gene is functionally imprinted in adult mouse brain. Mice deleted for all three subunits die at birth with a cleft palate, although there are rare survivors (approximately 5%) that do not have a cleft palate but do exhibit a neurological abnormality characterized by tremor, jerky gait, and runtiness. We have previously suggested that deficiency of the beta 3 subunit may be responsible for the clefting defect. Most notably, however, in this report we describe mice carrying two overlapping, complementing p deletions that fail to express the gamma 3 transcript, as well as mice from another line that express neither the gamma 3 nor alpha 5 transcripts. Surprisingly, mice from both of these lines are phenotypically normal and do not exhibit any of the neurological symptoms characteristic of the rare survivors that are deleted for all three (gamma 3, alpha 5, and beta 3) subunits. These mice therefore provide a whole-organism type A gamma-aminobutyric-acid receptor background that is devoid of any receptor subtypes that normally contain the gamma 3 and/or alpha 5 subunits. The absence of an overt neurological phenotype in mice lacking the gamma 3 and/or alpha 5 subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.