Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome
Summary: 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
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| Series: | HGG Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247723000702 |
| _version_ | 1827804694600220672 |
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| author | Yosuke Nishio Kohji Kato Frederic Tran Mau-Them Hiroshi Futagawa Chloé Quélin Saori Masuda Antonio Vitobello Shiomi Otsuji Hossam H. Shawki Hisashi Oishi Christel Thauvin-Robinet Toshiki Takenouchi Kenjiro Kosaki Yoshiyuki Takahashi Shinji Saitoh |
| author_facet | Yosuke Nishio Kohji Kato Frederic Tran Mau-Them Hiroshi Futagawa Chloé Quélin Saori Masuda Antonio Vitobello Shiomi Otsuji Hossam H. Shawki Hisashi Oishi Christel Thauvin-Robinet Toshiki Takenouchi Kenjiro Kosaki Yoshiyuki Takahashi Shinji Saitoh |
| author_sort | Yosuke Nishio |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-11T21:14:50Z |
| format | Article |
| id | doaj.art-500afd5a9bde413c8c9a8ccf0d6652d9 |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-03-11T21:14:50Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-500afd5a9bde413c8c9a8ccf0d6652d92023-09-29T04:45:10ZengElsevierHGG Advances2666-24772023-10-0144100238Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndromeYosuke Nishio0Kohji Kato1Frederic Tran Mau-Them2Hiroshi Futagawa3Chloé Quélin4Saori Masuda5Antonio Vitobello6Shiomi Otsuji7Hossam H. Shawki8Hisashi Oishi9Christel Thauvin-Robinet10Toshiki Takenouchi11Kenjiro Kosaki12Yoshiyuki Takahashi13Shinji Saitoh14Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, JapanDepartment of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan; Corresponding authorUnité Fonctionnelle 6254 d’Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, 21070 Dijon, France; INSERM UMR1231 GAD, 21000 Dijon, FranceDepartment of Clinical Genetics, Tokyo Metropolitan Children’s Medical Center, Tokyo 183-8561, JapanService de Génétique Clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, 35200 Rennes, FranceDepartment of Hematology and Oncology, Tokyo Metropolitan Children’s Medical Center, Tokyo 183-8561, JapanUnité Fonctionnelle 6254 d’Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, 21070 Dijon, France; INSERM UMR1231 GAD, 21000 Dijon, FranceDepartment of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, JapanDepartment of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya 467-8601, JapanDepartment of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya 467-8601, JapanUnité Fonctionnelle 6254 d’Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, 21070 Dijon, France; INSERM UMR1231 GAD, 21000 Dijon, France; Centre de Référence Maladies Rares “Anomalies du développement et syndromes malformatifs”, Centre de Génétique, FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, 21070 Dijon, FranceDepartment of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, JapanCenter for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, JapanDepartment of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8560, JapanDepartment of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247723000702 |
| spellingShingle | Yosuke Nishio Kohji Kato Frederic Tran Mau-Them Hiroshi Futagawa Chloé Quélin Saori Masuda Antonio Vitobello Shiomi Otsuji Hossam H. Shawki Hisashi Oishi Christel Thauvin-Robinet Toshiki Takenouchi Kenjiro Kosaki Yoshiyuki Takahashi Shinji Saitoh Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome HGG Advances |
| 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 |
| url | http://www.sciencedirect.com/science/article/pii/S2666247723000702 |
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