Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models
| Autor: | Hamid Meziane, Marie-Christine Birling, Olivia Wendling, Sophie Leblanc, Aline Dubos, Mohammed Selloum, Guillaume Pavlovic, Tania Sorg, Vera M. Kalscheuer, Pierre Billuart, Frédéric Laumonnier, Jamel Chelly, Hans van Bokhoven, Yann Herault |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Biomedicines, Vol 10, Iss 12, p 3148 (2022) |
| Druh dokumentu: | article |
| ISSN: | 10123148 2227-9059 |
| DOI: | 10.3390/biomedicines10123148 |
| Popis: | Major progress has been made over the last decade in identifying novel genes involved in neurodevelopmental disorders, although the task of elucidating their corresponding molecular and pathophysiological mechanisms, which are an essential prerequisite for developing therapies, has fallen far behind. We selected 45 genes for intellectual disabilities to generate and characterize mouse models. Thirty-nine of them were based on the frequency of pathogenic variants in patients and literature reports, with several corresponding to de novo variants, and six other candidate genes. We used an extensive screen covering the development and adult stages, focusing specifically on behaviour and cognition to assess a wide range of functions and their pathologies, ranging from basic neurological reflexes to cognitive abilities. A heatmap of behaviour phenotypes was established, together with the results of selected mutants. Overall, three main classes of mutant lines were identified based on activity phenotypes, with which other motor or cognitive deficits were associated. These data showed the heterogeneity of phenotypes between mutation types, recapitulating several human features, and emphasizing the importance of such systematic approaches for both deciphering genetic etiological causes of ID and autism spectrum disorders, and for building appropriate therapeutic strategies. |
| Databáze: | Directory of Open Access Journals |
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