Article ; Online: Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.
HGG advances
2023 Volume 4, Issue 4, Page(s) 100238
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Mice ; Animals ; Humans ; Female ; Microcephaly/genetics ; Gain of Function Mutation ; N-Myc Proto-Oncogene Protein/genetics ; Polydactyly/genetics ; Phenotype ; Megalencephaly/genetics ; Eyelids/abnormalities ; Intellectual Disability ; Tracheoesophageal Fistula ; Limb Deformities, Congenital |
| Chemical Substances | N-Myc Proto-Oncogene Protein ; MYCN protein, human |
| Language | English |
| Publishing date | 2023-09-14 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2666-2477 |
| ISSN (online) | 2666-2477 |
| DOI | 10.1016/j.xhgg.2023.100238 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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