MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome

Koji Kato, Fuyuki Miya, Nanako Hamada, Yutaka Negishi, Yoko Narumi-Kishimoto, Hiroshi Ozawa, Hidenori Ito, Ikumi Hori, Ayako Hattori, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Yonehiro Kanemura, Kenjiro Kosaki, Yoshiyuki Takahashi, Koh Ichi Nagata, Shinji Saitoh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of medical genetics
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Megalencephaly
Mutation
Polydactyly
Genes
Stem Cells
Exome
Corpus Callosum
Ubiquitination
Neurogenesis
Missense Mutation
Hydrocephalus
Neuroblastoma
Intellectual Disability
Cerebral Cortex
Cell Movement
Virulence
Embryonic Structures
Phosphorylation
Cell Proliferation
Brain

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome. / Kato, Koji; Miya, Fuyuki; Hamada, Nanako; Negishi, Yutaka; Narumi-Kishimoto, Yoko; Ozawa, Hiroshi; Ito, Hidenori; Hori, Ikumi; Hattori, Ayako; Okamoto, Nobuhiko; Kato, Mitsuhiro; Tsunoda, Tatsuhiko; Kanemura, Yonehiro; Kosaki, Kenjiro; Takahashi, Yoshiyuki; Nagata, Koh Ichi; Saitoh, Shinji.

In: Journal of medical genetics, 01.01.2018.

Research output: Contribution to journalArticle

Kato, K, Miya, F, Hamada, N, Negishi, Y, Narumi-Kishimoto, Y, Ozawa, H, Ito, H, Hori, I, Hattori, A, Okamoto, N, Kato, M, Tsunoda, T, Kanemura, Y, Kosaki, K, Takahashi, Y, Nagata, KI & Saitoh, S 2018, 'MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome', Journal of medical genetics. https://doi.org/10.1136/jmedgenet-2018-105487
Kato, Koji ; Miya, Fuyuki ; Hamada, Nanako ; Negishi, Yutaka ; Narumi-Kishimoto, Yoko ; Ozawa, Hiroshi ; Ito, Hidenori ; Hori, Ikumi ; Hattori, Ayako ; Okamoto, Nobuhiko ; Kato, Mitsuhiro ; Tsunoda, Tatsuhiko ; Kanemura, Yonehiro ; Kosaki, Kenjiro ; Takahashi, Yoshiyuki ; Nagata, Koh Ichi ; Saitoh, Shinji. / MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome. In: Journal of medical genetics. 2018.
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AU - Kato, Koji

AU - Miya, Fuyuki

AU - Hamada, Nanako

AU - Negishi, Yutaka

AU - Narumi-Kishimoto, Yoko

AU - Ozawa, Hiroshi

AU - Ito, Hidenori

AU - Hori, Ikumi

AU - Hattori, Ayako

AU - Okamoto, Nobuhiko

AU - Kato, Mitsuhiro

AU - Tsunoda, Tatsuhiko

AU - Kanemura, Yonehiro

AU - Kosaki, Kenjiro

AU - Takahashi, Yoshiyuki

AU - Nagata, Koh Ichi

AU - Saitoh, Shinji

PY - 2018/1/1

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N2 - 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.

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