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Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome
MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550848/ https://www.ncbi.nlm.nih.gov/pubmed/37710961 http://dx.doi.org/10.1016/j.xhgg.2023.100238 |
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author | Nishio, Yosuke Kato, Kohji Tran Mau-Them, Frederic Futagawa, Hiroshi Quélin, Chloé Masuda, Saori Vitobello, Antonio Otsuji, Shiomi Shawki, Hossam H. Oishi, Hisashi Thauvin-Robinet, Christel Takenouchi, Toshiki Kosaki, Kenjiro Takahashi, Yoshiyuki Saitoh, Shinji |
author_facet | Nishio, Yosuke Kato, Kohji Tran Mau-Them, Frederic Futagawa, Hiroshi Quélin, Chloé Masuda, Saori Vitobello, Antonio Otsuji, Shiomi Shawki, Hossam H. Oishi, Hisashi Thauvin-Robinet, Christel Takenouchi, Toshiki Kosaki, Kenjiro Takahashi, Yoshiyuki Saitoh, Shinji |
author_sort | Nishio, Yosuke |
collection | PubMed |
description | MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis. |
format | Online Article Text |
id | pubmed-10550848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-105508482023-10-06 Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome Nishio, Yosuke Kato, Kohji Tran Mau-Them, Frederic Futagawa, Hiroshi Quélin, Chloé Masuda, Saori Vitobello, Antonio Otsuji, Shiomi Shawki, Hossam H. Oishi, Hisashi Thauvin-Robinet, Christel Takenouchi, Toshiki Kosaki, Kenjiro Takahashi, Yoshiyuki Saitoh, Shinji HGG Adv Article MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis. Elsevier 2023-09-14 /pmc/articles/PMC10550848/ /pubmed/37710961 http://dx.doi.org/10.1016/j.xhgg.2023.100238 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Nishio, Yosuke Kato, Kohji Tran Mau-Them, Frederic Futagawa, Hiroshi Quélin, Chloé Masuda, Saori Vitobello, Antonio Otsuji, Shiomi Shawki, Hossam H. Oishi, Hisashi Thauvin-Robinet, Christel Takenouchi, Toshiki Kosaki, Kenjiro Takahashi, Yoshiyuki Saitoh, Shinji Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title | Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title_full | Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title_fullStr | Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title_full_unstemmed | Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title_short | Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome |
title_sort | gain-of-function mycn causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of feingold syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550848/ https://www.ncbi.nlm.nih.gov/pubmed/37710961 http://dx.doi.org/10.1016/j.xhgg.2023.100238 |
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