MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.
J Med Genet
; 56(6): 388-395, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30573562
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Predisposição Genética para Doença
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Estudos de Associação Genética
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Megalencefalia
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Proteína Proto-Oncogênica N-Myc
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Mutação com Ganho de Função
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Adolescent
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Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão