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Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
N. Voisin, RE. Schnur, S. Douzgou, SM. Hiatt, CF. Rustad, NJ. Brown, DL. Earl, B. Keren, O. Levchenko, S. Geuer, S. Verheyen, D. Johnson, YA. Zarate, M. Hančárová, DJ. Amor, EM. Bebin, J. Blatterer, A. Brusco, G. Cappuccio, J. Charrow, N....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
Wellcome Trust - United Kingdom
UM1 HG007301
NHGRI NIH HHS - United States
NV17-29423A
MZ0
CEP Register
Digital library NLK
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- MeSH
- Zebrafish genetics MeSH
- Child MeSH
- Epilepsy complications genetics MeSH
- Phenotype MeSH
- Gene Frequency MeSH
- Fused Kidney genetics MeSH
- Nuclear Proteins chemistry deficiency genetics MeSH
- Infant MeSH
- Humans MeSH
- Intellectual Disability genetics MeSH
- Mutation, Missense * MeSH
- Adolescent MeSH
- Young Adult MeSH
- Evolution, Molecular MeSH
- Models, Molecular MeSH
- Mice MeSH
- Brain Diseases etiology genetics MeSH
- Osteochondrodysplasias genetics MeSH
- Child, Preschool MeSH
- Amino Acid Sequence MeSH
- Protein Stability MeSH
- Syndrome MeSH
- Transcriptional Elongation Factors chemistry genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
Bioinformatics Competence Center University of Lausanne Lausanne 1015 Switzerland
Center for Integrative Genomics University of Lausanne Lausanne 1015 Switzerland
Cooper Medical School of Rowan University Division of Genetics Camden NJ 08103 USA
Department of Genetics University of Alabama at Birmingham Birmingham AL 35233 USA
Department of Medical Genetics Oslo University Hospital 0424 Oslo Norway
Department of Medical Genetics Telemark Hospital Trust 3710 Skien Norway
Department of Medical Sciences University of Torino Torino 10126 Italy
Department of Medicine Columbia University New York NY 10032 USA
Department of Neurology University of Alabama at Birmingham Birmingham AL 35294 USA
Department of Pediatrics Columbia University New York NY 10032 USA
Department of Radiology Oslo University Hospital 0424 Oslo Norway
Department of Translational Medicine Section of Pediatrics Federico 2 University Naples 80131 Italy
GeneDx Gaithersburg MD 20877 USA
Genetics Department Lyon University Hospital Lyon 69007 France
HudsonAlpha Institute for Biotechnology Huntsville AL 35806 USA
Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch 67404 France
Institute for Maternal and Child Health IRCCS Burlo Garofolo Trieste 34100 Italy
Institute for Medical and Human Genetics Charité Universitätsmedizin Berlin Berlin 10117 Germany
Integris Pediatric Neurology Oklahoma City OK 73112 USA
Max Planck Institute for Molecular Genetics Berlin 14195 Germany
Medical Genetics Unit Città della Salute e della Scienza University Hospital Torino 10126 Italy
Murdoch Children's Research Institute Flemington Road Parkville VIC 3052 Australia
New York Medical College Valhalla NY 10595 USA
Protein Analysis Facility University of Lausanne Lausanne 1015 Switzerland
Research Centre for Medical Genetics Moscow 115522 Russia
Seattle Children's Seattle WA 98105 USA
Secteur Génétique CHU Reims EA3801 SFR CAPSANTE 51092 Reims France
Sheffield Clinical Genetics Service Sheffield S10 2TQ UK
Swiss Institute of Bioinformatics Lausanne 1015 Switzerland
Telethon Institute of Genetics and Medicine Pozzuoli Naples 80078 Italy
Victorian Clinical Genetics Services Flemington Road Parkville VIC 3052 Australia
References provided by Crossref.org
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