MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis
MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis
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DOI：
10.1093/brain/awz379
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发表时间：
2020-01-01
期刊：
影响因子：
14.5
通讯作者：
Gordon, Christopher T.
中科院分区：
文献类型：
--
作者：
Mak, Christopher C. Y.;Doherty, Dan;Gordon, Christopher T.
MN1编码一种与其他蛋白无同源性的转录共调节因子，先前与急性髓性白血病和腭发育有关。在具有可变神经发育-智力异常和非特异性面部特征的个体中，已经报道了大量的croinp: wing， MN1缺失。我们在一个23人的队列中发现了一组MN1从头截断突变，这些人的面部特征非常相似，尤其是脸中发育不全，智力残疾伴严重的表达性语言迟缓。在8/21例患者中，影像学显示了一种非典型的菱形脑突触，这是一种独特的脑畸形，其特征是小脑蚓部部分或完全丧失，小脑半球融合。菱形脑突触症以前没有已知的明确的遗传或环境原因。其他常见的特征包括周围型多小回畸形、后斜突异常和持续性三叉动脉，MN1仅由两个外显子编码。所有突变，包括在8/21先证者中观察到的复发变异p.a g1295*，都落在eNon 1的末端外显子或极端3'区，因此预测会导致逃离无义介导的mRNA衰变。这在三个个体的成纤维细胞中得到证实。我们认为，MN1 c -末端截断（MCTT）综合征不是由于MN1单倍功能不全，而是显性作用的c -末端MN1蛋白的结果。我们的数据表明，MN1在人类颅面和大脑发育中起着关键作用，并为了解菱形脑突触的生物学机制打开了大门。
MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions cricoinp:wiing, MN1 have here reported in individuals with variable neurodevclop-mental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/21 individuals. rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery, MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of eNon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. we propose that the condition described here, MN1 C-termirim truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominandy acting C-terminally MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door t understanding the biological mechanisms underlying rhombencephalosynapsis.