Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
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Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3 . We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3 . Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3 . Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Variant-specific pathophysiological mechanisms of <i>AFF3</i> differently influence transcriptome profiles
- Date Crossref
- 17/01/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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University of Lausanne Center for Integrative Genomics pays non établi dans la noticeUniversité ou école supérieure
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École Polytechnique Fédérale de Lausanne Bioinformatics Competence Center pays non établi dans la noticeUniversité ou école supérieure
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Azienda Ospedaliera Citta' della Salute e della Scienza di Torino pays non établi dans la noticeÉtablissement de santé
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University of Turin Department of Neurosciences Rita Levi-Montalcini pays non établi dans la noticeUniversité ou école supérieure
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Leipzig University pays non établi dans la noticeUniversité ou école supérieure
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Gemeinschaftskrankenhaus Herdecke pays non établi dans la noticeÉtablissement de santé
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University of Utah Pediatric Neurology pays non établi dans la noticeUniversité ou école supérieure
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Vanderbilt University Medical Center Department of Pediatrics pays non établi dans la noticeÉtablissement de santé
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Radboud University Nijmegen pays non établi dans la noticeUniversité ou école supérieure
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Radboud University Medical Center Department of Human Genetics pays non établi dans la noticeOrganisme public
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Zuidwester pays non établi dans la noticeInstitution
Center for Integrative Genomics — University of Lausanne, Bioinformatics Competence Center — École Polytechnique Fédérale de Lausanne et Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, avec 9 autres affiliations.
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