PHENOTYPIC CONSEQUENCES OF DELETION OF THE GAMMA(3)-SUBUNIT, ALPHA(5)-SUBUNIT, OR BETA(3)-SUBUNIT OF THE TYPE-A GAMMA-AMINOBUTYRIC-ACID RECEPTOR IN MICE
PHENOTYPIC CONSEQUENCES OF DELETION OF THE GAMMA(3)-SUBUNIT, ALPHA(5)-SUBUNIT, OR BETA(3)-SUBUNIT OF THE TYPE-A GAMMA-AMINOBUTYRIC-ACID RECEPTOR IN MICE
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DOI：
10.1073/pnas.91.7.2815
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发表时间：
1994-03-29
影响因子：
11.1
通讯作者：
RINCHIK, EM
中科院分区：
文献类型：
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作者：
CULIAT, CT;STUBBS, LJ;RINCHIK, EM
已知分别编码A型γ-氨基丁酸受体的γ 3、α 5和β 3亚基的三个基因（Gabrg 3、Gabra 5和Gabrb 3）在小鼠7号染色体中的红眼稀释（p）位点附近作图。该区域与人类15号染色体的一个片段具有同源性，该片段与Angelman综合征（一种遗传性神经行为障碍）有关。通过将Gabrg 3定位在一组p位点缺失上，我们确定了该簇内基因的顺序为着丝粒-p（D15 S12 h）-Gabrg 3-Gabra 5-Gabrb-3-端粒。与Gabrb 3一样，Gabra 5和Gabrg 3基因在成年小鼠大脑中都没有功能印记。缺失所有三个亚基的小鼠在出生时死于腭裂，尽管有罕见的幸存者（几乎等于5%）没有腭裂，但确实表现出以震颤，步态不稳和矮小为特征的神经异常。我们以前曾提出，β 3亚基的缺陷可能是造成裂缝缺陷的原因。然而，最值得注意的是，在这份报告中，我们描述了小鼠携带两个重叠的，互补的p缺失，不能表达γ 3转录，以及小鼠从另一个线既不表达γ 3也不α 5转录。令人惊讶的是，来自这两个品系的小鼠在表型上都是正常的，并且没有表现出任何罕见的幸存者所特有的神经症状，这些幸存者缺失了所有三个（γ 3、α 5和β 3）亚基。因此，这些小鼠提供了一种全生物体A型γ-氨基丁酸受体背景，其缺乏通常含有γ 3和/或α 5亚基的任何受体亚型。在缺乏γ 3和/或α 5亚基的小鼠中缺乏明显的神经学表型也表明这些基因中的突变不太可能为人类中的Angelman综合征提供有用的动物模型。
Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the gamma3, alpha5, and beta3 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-Gabrb-3-telomere. 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 (almost-equal-to 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 beta3 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 gamma3 transcript, as well as mice from another line that express neither the gamma3 nor alpha5 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 (gamma3, alpha5, and beta3) 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 gamma3 and/or alpha5 subunits. The absence of an overt neurological phenotype in mice lacking the gamma3 and/or alpha5 subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.