Galnt17 loss-of-function leads to developmental delay and abnormal coordination, activity, and social interactions with cerebellar vermis pathology.
Galnt17 loss-of-function leads to developmental delay and abnormal coordination, activity, and social interactions with cerebellar vermis pathology.
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DOI：
10.1016/j.ydbio.2022.08.002
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发表时间：
2022-10
影响因子：
2.7
通讯作者：
Stubbs, Lisa J.
中科院分区：
文献类型：
--
作者：
Chen, Chih-Ying;Seward, Christopher H.;Song, Yunshu;Inamdar, Manasi;Leddy, Analise M.;Zhang, Huimin;Yoo, Jennifer;Kao, Wei-Chun;Pawlowski, Hanna;Stubbs, Lisa J.
GALNT17 编码一种 N-乙酰半乳糖胺基转移酶 (GalNAc-T) 蛋白，专门参与靶蛋白的粘蛋白型 O-连接糖基化，这一过程对于细胞粘附、细胞信号传导、神经递质活性、神经突生长和神经突传感非常重要。 GALNT17，也称为 WBSCR17，位于威廉姆斯-博伊伦综合征 (WBS) 关键区域的边缘，邻近 AUTS2 基因座，该基因组区域与神经发育表型相关，被认为是共同调控的。尽管之前的数据表明 Galnt17 与神经发育有关，但该基因的体内功能尚未得到研究。在这项研究中，我们分析了 Galnt17 敲除 (Galnt17−/−) 小鼠表现出的行为、脑病理学和分子表型。我们发现 Galnt17−/− 突变体在小脑蚓部表现出发育性神经病理学，以及异常活动、协调和社交互动缺陷。转录组和蛋白质分析显示，发育中的突变小脑中粘蛋白型 O-糖基化和硫酸乙酰肝素合成均减少，同时神经元分化、轴突寻路和突触信号传导的中心通路受到破坏，这与突变神经病理学一致。这些大脑和行为表型以及分子数据证实了 Galnt17 在大脑发育中的特定作用，并为可能导致某些 WBS 和 AUTS2 综合征患者表型的因素提供了新线索。
GALNT17 encodes a N-acetylgalactosaminyltransferase (GalNAc-T) protein specifically involved in mucin-type O-linked glycosylation of target proteins, a process important for cell adhesion, cell signaling, neurotransmitter activity, neurite outgrowth, and neurite sensing. GALNT17, also known as WBSCR17, is located at the edge of the Williams-Beuren Syndrome (WBS) critical region and adjacent to the AUTS2 locus, genomic regions associated with neurodevelopmental phenotypes that are thought to be co-regulated. Although previous data have implicated Galnt17 in neurodevelopment, the in vivo functions of this gene have not been investigated. In this study, we have analyzed behavioral, brain pathology, and molecular phenotypes exhibited by Galnt17 knockout (Galnt17−/−) mice. We show that Galnt17−/− mutants exhibit developmental neuropathology within the cerebellar vermis, along with abnormal activity, coordination, and social interaction deficits. Transcriptomic and protein analysis revealed reductions in both mucin type O-glycosylation and heparan sulfate synthesis in the developing mutant cerebellum along with disruption of pathways central to neuron differentiation, axon pathfinding, and synaptic signaling, consistent with the mutant neuropathology. These brain and behavioral phenotypes and molecular data confirm a specific role for Galnt17 in brain development and suggest new clues to factors that could contribute to phenotypes in certain WBS and AUTS2 syndrome patients.
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DOI：
10.1016/j.neo.2018.08.006
发表时间：
2018-10
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Deng B;Tarhan YE;Ueda K;Ren L;Katagiri T;Park JH;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
5.6
作者：
Ferreira IG;Pucci M;Venturi G;Malagolini N;Chiricolo M;Dall'Olio F
通讯作者：
Dall'Olio F
影响因子：
3.5
作者：
Bennett, EP;Hassan, H;Clausen, H
通讯作者：
Clausen, H
影响因子：
3.5
作者：
Cheng, LM;Tachibana, K;Narimatsu, H
通讯作者：
Narimatsu, H
影响因子：
7
作者：
Ishihama, Y;Oda, Y;Mann, M
通讯作者：
Mann, M