超越癫痫和自闭症：GABRB3功能紊乱导致眼部色素沉着不足。
Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.
作者信息
Delahanty Ryan J, Zhang Yanfeng, Bichell Terry Jo, Shen Wangzhen, Verdier Kelienne, Macdonald Robert L, Xu Lili, Boyd Kelli, Williams Janice, Kang Jing-Qiong
机构信息
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA; Department of Human Genetics, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
出版信息
Cell Rep. 2016 Dec 20;17(12):3115-3124. doi: 10.1016/j.celrep.2016.11.067.
Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3 mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.
眼部色素沉着减少在天使综合征（AS）和普拉德-威利综合征（PWS）中很常见，长期以来一直被认为是由OCA2缺失引起的。GABRB3位于15q11 - 13区域，两侧分别是UBE3A、GABRA5、GABRG3和OCA2。GABRB3的突变经常与癫痫和自闭症相关，这与其在神经发育中的作用一致。我们在此报告了一种小鼠的显著表型，其中单独缺失Gabrb3会由于黑素小体萎缩导致视网膜色素沉着几乎完全丧失，电子显微镜证实了这一点。通过外显子组和RNA测序，我们证实只有Gabrb3基因被破坏，而Oca2基因是完整的。然而，在Gabrb3基因敲除小鼠中，Oca2和其他与Gabrb3相邻基因的mRNA丰度显著降低，表明该区域存在复杂的转录调控。这些结果表明，GABRB3功能受损会下调OCA2，并间接导致AS和PWS中的眼部色素减退和视觉缺陷。
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