دورية أكاديمية
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
| العنوان: | CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology |
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| المؤلفون: | Oppermann, H., Marcos-Grañeda, E., Weiss, L. A., Gurnett, C. A., Jelsig, A. M., Vineke, S. H., Isidor, B., Mercier, S., Magnussen, K., Zacher, P., Hashim, M., Pagnamenta, A. T., Race, S., Srivastava, S., Frazier, Z., Maiwald, R., Pergande, M., Milani, D., Rinelli, M., Levy, J., Krey, I., Fontana, P., Lonardo, F., Riley, S., Kretzer, J., Rankin, J., Reis, L. M., Semina, E. V., Reuter, M. S., Scherer, S. W., Iascone, M., Weis, D., Fagerberg, C. R., Brasch-Andersen, C., Hansen, L. K., Kuechler, A., Noble, N., Gardham, A., Tenney, J., Rathore, G., Beck-Woedl, S., Haack, T. B., Pavlidou, D. C., Atallah, I., Vodopiutz, J., Janecke, A. R., Hsieh, T. C., Lesmann, H., Klinkhammer, H., Krawitz, P. M., Lemke, J. R., Jamra, R. A., Nieto, M., Tümer, Z., Platzer, K. |
| بيانات النشر: | Nature |
| سنة النشر: | 2023 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| الوصف: | Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1(+/-) mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1(+/-) mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1(+/-) mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1(+/-) brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course. ; Accepted version (6 month embargo), submitted version ; RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.1038/s41431-023-01445-2Test; Oppermann H, Marcos-Grañeda E, Weiss LA, Gurnett CA, Jelsig AM, Vineke SH, et al. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology. European journal of human genetics : EJHG. 2023.; European journal of human genetics; https://hdl.handle.net/11287/622952Test |
| DOI: | 10.1038/s41431-023-01445-2 |
| الإتاحة: | https://doi.org/10.1038/s41431-023-01445-2Test https://hdl.handle.net/11287/622952Test |
| حقوق: | © 2023. The Author(s). |
| رقم الانضمام: | edsbas.35D07A2D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41431-023-01445-2 |
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