Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies
| Autor: | Noelle Lachaussée, Géraldine Mollet, Maria Clara Guida, Olivier Gribouval, Olivia Boyer, Corinne Antignac, Thierry Billette de Villemeur, Martin Helmstädter, Caroline Nava, Rolf Bodmer, Alexandra Afenjar, Jane Juusola, Patrick Nitschke, Sara Gonçalves, Boris Keren, Patricia G. Wheeler, Marina Charbit, Tobias B. Huber, Marie-Claire Gubler, Julie Patat, Marlène Rio, Christelle Arrondel, Matias Simons, Christine Bole-Feysot, Devon Haynes |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research lcsh:QH426-470 Adolescent Heart Diseases DNA Mutational Analysis Corpus callosum Bioinformatics Cell Line 03 medical and health sciences Text mining Cataracts Genetics medicine Animals Drosophila Proteins Humans Abnormalities Multiple p300-CBP Transcription Factors Clinical phenotype Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics Cells Cultured Proteinuria biology business.industry Homozygote Correction medicine.disease biology.organism_classification Pedigree lcsh:Genetics 030104 developmental biology Phenotype ADD3 Nasal Diseases Mutation Kidney Failure Chronic Calmodulin-Binding Proteins Drosophila Female medicine.symptom Drosophila melanogaster business |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 14, Iss 10, p e1007748 (2018) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders. |
| Databáze: | OpenAIRE |
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