| dc.contributor.author | Sissy Bassani | |
| dc.contributor.author | Jacqueline Chrast | |
| dc.contributor.author | Giovanna Ambrosini | |
| dc.contributor.author | Norine Voisin | |
| dc.contributor.author | Frédéric Schütz | |
| dc.contributor.author | Alfredo Brusco | |
| dc.contributor.author | Fabio Sirchia | |
| dc.contributor.author | Lydia Turban | |
| dc.contributor.author | Susanna Schubert | |
| dc.contributor.author | Rami Abou Jamra | |
| dc.contributor.author | Jan-Ulrich Schlump | |
| dc.contributor.author | Desiree DeMille | |
| dc.contributor.author | Pinar Bayrak-Toydemir | |
| dc.contributor.author | Gary Rex Nelson | |
| dc.contributor.author | Kristen Nicole Wong | |
| dc.contributor.author | Laura Duncan | |
| dc.contributor.author | Mackenzie Mosera | |
| dc.contributor.author | Christian Gilissen | |
| dc.contributor.author | Lisenka E. L. M. Vissers | |
| dc.contributor.author | Rolph Pfundt | |
| dc.contributor.author | Rogier Kersseboom | |
| dc.contributor.author | Hilde Yttervik | |
| dc.contributor.author | Geir Åsmund Myge Hansen | |
| dc.contributor.author | Marie Falkenberg Smeland | |
| dc.contributor.author | Kameryn M. Butler | |
| dc.contributor.author | Michael J. Lyons | |
| dc.contributor.author | Claudia M. B. Carvalho | |
| dc.contributor.author | Chaofan Zhang | |
| dc.contributor.author | James R. Lupski | |
| dc.contributor.author | Lorraine Potocki | |
| dc.contributor.author | Leticia Flores-Gallegos | |
| dc.contributor.author | Rodrigo Morales-Toquero | |
| dc.contributor.author | Florence Petit | |
| dc.contributor.author | Binnaz Yalcin | |
| dc.contributor.author | Annabelle Tuttle | |
| dc.contributor.author | Houda Zghal Elloumi | |
| dc.contributor.author | Lane McCormick | |
| dc.contributor.author | Mary Kukolich | |
| dc.contributor.author | Oliver Klaas | |
| dc.contributor.author | Judit Horvath | |
| dc.contributor.author | Marcello Scala | |
| dc.contributor.author | Michele Iacomino | |
| dc.contributor.author | Francesca Operto | |
| dc.contributor.author | Federico Zara | |
| dc.contributor.author | Karin Writzl | |
| dc.contributor.author | Aleš Maver | |
| dc.contributor.author | Maria K. Haanpää | |
| dc.contributor.author | Pia Pohjola | |
| dc.contributor.author | Harri Arikka | |
| dc.contributor.author | Anneke J. A. Kievit | |
| dc.contributor.author | Camilla Calandrini | |
| dc.contributor.author | Christian Iseli | |
| dc.contributor.author | Nicolas Guex | |
| dc.contributor.author | Alexandre Reymond | |
| dc.contributor.other | Center for Integrative Genomics, University of Lausanne | |
| dc.contributor.other | Center for Integrative Genomics, University of Lausanne | |
| dc.contributor.other | Bioinformatics Competence Center, University of Lausanne | |
| dc.contributor.other | Center for Integrative Genomics, University of Lausanne | |
| dc.contributor.other | Biostatistics Platform, University of Lausanne | |
| dc.contributor.other | Department of Neurosciences Rita Levi-Montalcini, University of Turin | |
| dc.contributor.other | Department of Neurosciences Rita Levi-Montalcini, University of Turin | |
| dc.contributor.other | Institute of Human Genetics, University of Leipzig Medical Center | |
| dc.contributor.other | Institute of Human Genetics, University of Leipzig Medical Center | |
| dc.contributor.other | Institute of Human Genetics, University of Leipzig Medical Center | |
| dc.contributor.other | Department of Pediatrics, Centre for Neuromedicine | |
| dc.contributor.other | Genomics Analysis 396, ARUP Laboratories | |
| dc.contributor.other | Pediatric Neurology, University of Utah School of Medicine | |
| dc.contributor.other | Pediatric Neurology, University of Utah School of Medicine | |
| dc.contributor.other | Pediatric Neurology, University of Utah School of Medicine | |
| dc.contributor.other | Department of Pediatrics, Medical Center North, Vanderbilt University Medical Center | |
| dc.contributor.other | Department of Pediatrics, Medical Center North, Vanderbilt University Medical Center | |
| dc.contributor.other | Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center | |
| dc.contributor.other | Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center | |
| dc.contributor.other | Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center | |
| dc.contributor.other | Center for Genetic Developmental Disorders Southwest | |
| dc.contributor.other | Department of Medical Genetics, University Hospital of North Norway | |
| dc.contributor.other | Department of Medical Genetics, University Hospital of North Norway | |
| dc.contributor.other | Department of Pediatric Rehabilitation, University Hospital of North Norway | |
| dc.contributor.other | Greenwood Genetic Center | |
| dc.contributor.other | Greenwood Genetic Center | |
| dc.contributor.other | Pacific Northwest Research Institute (PNRI) | |
| dc.contributor.other | Department of Molecular and Human Genetics, Baylor College of Medicine | |
| dc.contributor.other | Department of Molecular and Human Genetics, Baylor College of Medicine | |
| dc.contributor.other | Department of Molecular and Human Genetics, Baylor College of Medicine | |
| dc.contributor.other | Hospital Ángeles Puebla | |
| dc.contributor.other | Hospital Ángeles Puebla | |
| dc.contributor.other | CHU Lille, Clinique de Génétique | |
| dc.contributor.other | Inserm UMR1231, University of Burgundy | |
| dc.contributor.other | GeneDx | |
| dc.contributor.other | GeneDx | |
| dc.contributor.other | Department of Genetics, Cook Children’s Medical Center, Cook Children’s Health Care System | |
| dc.contributor.other | Department of Genetics, Cook Children’s Medical Center, Cook Children’s Health Care System | |
| dc.contributor.other | Institute for Human Genetics, University Hospital Muenster | |
| dc.contributor.other | Institute for Human Genetics, University Hospital Muenster | |
| dc.contributor.other | Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa | |
| dc.contributor.other | Medical Genetics Unit, IRCCS Istituto Giannina Gaslini | |
| dc.contributor.other | Department of Medicine, Child and Adolescent Neuropsychiatry Unit, Surgery and Dentistry, University of Salerno | |
| dc.contributor.other | Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa | |
| dc.contributor.other | Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana | |
| dc.contributor.other | Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana | |
| dc.contributor.other | Department of Genomics, Turku University Hospital, Turku, Finland; University of Turku | |
| dc.contributor.other | Department of Genomics, Turku University Hospital, Turku, Finland; University of Turku | |
| dc.contributor.other | Department of Pediatric Neurology, Turku University Hospital, Turku, Finland; University of Turku | |
| dc.contributor.other | Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam | |
| dc.contributor.other | Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam | |
| dc.contributor.other | Bioinformatics Competence Center, University of Lausanne | |
| dc.contributor.other | Bioinformatics Competence Center, University of Lausanne | |
| dc.contributor.other | Center for Integrative Genomics, University of Lausanne | |
| dc.date.accessioned | 2024-06-02T11:28:57Z | |
| dc.date.accessioned | 2025-10-08T08:22:43Z | |
| dc.date.available | 2025-10-08T08:22:43Z | |
| dc.date.issued | 01-05-2024 | |
| dc.identifier.uri | http://digilib.fisipol.ugm.ac.id/repo/handle/15717717/35660 | |
| dc.description.abstract | 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 mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging 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 Loss-of-Function (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 rescue these phenotypes. 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 + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP 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. | |
| dc.language.iso | EN | |
| dc.publisher | BMC | |
| dc.subject.lcc | Medicine | |
| dc.title | Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles | |
| dc.type | Article | |
| dc.description.keywords | Mesomelic dysplasia | |
| dc.description.keywords | Horseshoe kidney | |
| dc.description.keywords | Intellectual disability | |
| dc.description.keywords | Transcriptome | |
| dc.description.keywords | Zebrafish model | |
| dc.description.pages | 1-18 | |
| dc.description.doi | 10.1186/s13073-024-01339-y | |
| dc.title.journal | Genome Medicine | |
| dc.identifier.e-issn | 1756-994X | |
| dc.identifier.oai | 0358fc56f6054b188a138c71c996e968 | |
| dc.journal.info | Volume 16, Issue 1 | |
