Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Roche Pharma Research and Early Development, Basel, Switzerland; Center for Autism Research and Treatment, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles.
Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Roche Pharma Research and Early Development, Basel, Switzerland.
Biol Psychiatry. 2019 May 1;85(9):752-759. doi: 10.1016/j.biopsych.2019.01.008. Epub 2019 Jan 19.
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 (β3, α5, γ3). 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.
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).
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.
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.
Angelman 综合征（AS）是一种严重的神经发育障碍，由 UBE3A 基因的中断或 15 号染色体 15q11-q13 的缺失引起，该缺失包括 UBE3A 和其他几个基因，包括 GABRB3、GABRA5 和 GABRG3，它们编码γ-氨基丁酸 A 型受体亚基（β3、α5、γ3）。缺失的个体通常比其他基因型的个体受损更严重，但潜在的病理生理学仍知之甚少。在这里，我们使用脑电图（EEG）来检验这样一个假设，即在 15q11-q13 上的除 UBE3A 以外的基因导致 AS 基因型之间的病理生理学差异。
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）和无 Angelman 综合征的典型发育儿童（n=48）的临床 EEG 记录的频谱功率。
我们发现与非缺失基因型相比，缺失基因型的θ波功率（峰频率：5.3 Hz）升高，β波功率（峰频率：23 Hz）降低，两种基因型都存在过多的宽带 EEG 功率（1-32 Hz），在 delta 频率范围内（峰频率：2.8 Hz）达到峰值，这种情况在两个基因型中都存在，但在年龄较小的儿童中，缺失基因型更为明显。
我们的研究结果为非 UBE3A 神经元病理生理学在缺失 AS 中的贡献提供了强有力的证据，并表明 GABRB3-GABRA5-GABRG3 基因簇的半合子状态导致异常的θ和β EEG 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发展具有直接影响。
