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.
- missense mutation
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Patient consent for publication Obtained.
Contributors SS was responsible for the concept and design of the study. KoK, KN and SS drafted the main manuscript. KoK, FM, NH, YN, HI, IH, KN and SS analysed and interpreted the data. KoK, YK, HO and SS contributed clinical data. AH, NO, MK, TT, YK, KeK and YT revised the manuscript and made comments on the structure, details and grammar of the article.
Funding This study was partially supported by the JSPS KAKENHI (grant number JP16K15530) (SS) and by the Program for an Integrated Database of Clinical and Genomic Information from the Japanese Agency for Medical Research and Development, AMED (SS).
Competing interests None declared.
Ethics approval This study was approved by the Ethical Committee for the Study of Human Gene Analysis at Nagoya City University Graduate School of Medical Sciences.
Provenance and peer review Not commissioned; externally peer reviewed.
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