MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome
MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome
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DOI：
10.1136/jmedgenet-2018-105487
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发表时间：
2019-06-01
影响因子：
4
通讯作者：
Saitoh, Shinji
中科院分区：
文献类型：
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作者：
Kato, Kohji;Miya, Fuyuki;Saitoh, Shinji
背景在这项研究中，我们的目的是确定一个未确诊的神经发育障碍患者的致病基因异常，包括巨脑畸形、脑室肥大、胼胝体发育不全、智力残疾、多指畸形和神经母细胞瘤。方法采用基于Trio的全外显子组测序技术，对致病基因突变进行鉴定。进行了生化和细胞生物学分析，以阐明所确定的基因突变的病理生理学意义。结果我们确定了一个杂合错义突变（c.173 C>T; p.Thr58Met）在MYCN基因，在Thr 58磷酸化位点必需的泛素化和随后的MYCN降解。突变体MYCN（MYCN-T58 M）在Thr 58处不可磷酸化，随后在细胞中积累，并且似乎在体外诱导神经元祖细胞和干细胞中的CCND 1和CCND 2表达。MyCN模仿p.Thr58Met突变过表达也促进神经元细胞增殖，并影响神经元细胞迁移在小鼠胚胎corticogenesis in mouse embryos.Conclusions我们确定了一个从头c.173C>T.突变MYCN导致稳定和积累的MYCN蛋白，导致CCND 1和CCND 2的表达延长。这可能会促进大脑皮层发育中的神经发生，导致巨脑畸形。虽然已知MYCN中的功能丧失突变会导致Feingold综合征，但这是首次报告在患有新型巨脑畸形综合征的患者中发现MYCN中的生殖系功能获得突变，该综合征类似于但不同于CCND 2相关的巨脑-多小脑回-多指-脑积水综合征。这里获得的数据为MYCN在大脑发育中的关键作用以及MYCN缺陷的后果提供了新的见解。
Background In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism.Methods Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation.Results We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos.Conclusions We identified a de novo c.173C>T.mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.