Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes
Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes
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DOI：
10.1016/j.biopsych.2019.01.008
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发表时间：
2019-05-01
影响因子：
10.6
通讯作者：
Hipp, Joerg F.
中科院分区：
文献类型：
--
作者：
Frohlich, Joel;Miller, Meghan T.;Hipp, Joerg F.
背景：天使综合征（AS）是一种严重的神经发育障碍，由 UBE3A 基因破坏或 15 号染色体 15q11-q13 缺失引起，该基因包含 UBE3A 和其他几个基因，包括编码 γ-氨基丁酸 A 型受体亚基（β 3、α 5、γ 3）的 GABRB3、GABRA5、GABRG3。具有缺失的个体通常比具有其他基因型的个体受到更严重的损害，但潜在的病理生理学仍然很大程度上未知。在这里，我们使用脑电图 (EEG) 来检验以下假设：位于 15q11-q13 上的 UBE3A 以外的基因会导致 AS 基因型之间的病理生理学差异。方法：我们比较了具有缺失基因型 (n = 37) 或非缺失基因型 (n = 21) 的儿童（1-18 岁）的临床脑电图记录的频谱功率，以及无天使综合征的典型发育儿童 (n = 48). 结果：我们发现与非删除基因型相比，删除基因型的 θ 功率（峰值频率：5.3 Hz）升高，β 功率降低（峰值频率：23 Hz），并且在 delta 频率范围（峰值频率：2.8 Hz）中出现过多的宽带脑电图功率（1-32 Hz）峰值，两种基因型共有，但删除基因型在年轻时更强。结论：我们的结果提供了强有力的证据。非 UBE3A 神经元病理生理学在缺失 AS 中的贡献的证据，并表明 GABRB3-GABRA5-GABRG3 基因簇的半合性导致异常的 θ 和 β 脑电图振荡，这可能是更严重的临床表型的基础。我们的工作提高了对 AS 病理生理学的理解，并对 AS 治疗和生物标志物的开发具有直接影响。
BACKGROUND: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (beta 3, alpha 5, gamma 3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes.METHODS: We compared spectral power of clinical EEG recordings from children (1-18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48).RESULTS: We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1-32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages.CONCLUSIONS: Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.