MYCNde novo gain-of-function mutation in a patient with a novel megalencephaly syndrome
Autor: | Mitsuhiro Kato, Koh-ichi Nagata, Nobuhiko Okamoto, Yoko Narumi-Kishimoto, Yonehiro Kanemura, Hiroshi Ozawa, Hidenori Ito, Kohji Kato, Ikumi Hori, Kenjiro Kosaki, Shinji Saitoh, Yoshiyuki Takahashi, Tatsuhiko Tsunoda, Nanako Hamada, Yutaka Negishi, Ayako Hattori, Fuyuki Miya |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Mutation Gene Abnormality 030105 genetics & heredity Gene mutation Biology medicine.disease_cause medicine.disease 03 medical and health sciences 030104 developmental biology Neurodevelopmental disorder Neuroblastoma Genetics medicine Cancer research Missense mutation Megalencephaly neoplasms N-Myc Genetics (clinical) |
Zdroj: | Journal of Medical Genetics. 56:388-395 |
ISSN: | 1468-6244 0022-2593 |
Popis: | BackgroundIn 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.MethodsTrio-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.ResultsWe identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in theMYCNgene, 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.ConclusionsWe identified a de novo c.173C>T mutation inMYCNwhich 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 inMYCNare known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation inMYCNidentified 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. |
Databáze: | OpenAIRE |
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