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PLoS Genet. 2018 May 16;14(5):e1007386. doi: 10.1371/journal.pgen.1007386. eCollection 2018 May.

A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

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Laboratory of Hereditary Kidney Diseases, Institut National de la Santé et de la Recherche Médicale (Inserm) UMR1163, Imagine Institute, Paris, France.
Laboratory of Epithelial Biology and Disease, Institut National de la Santé et de la Recherche Médicale (Inserm) UMR1163, Imagine Institute, Paris, France.
Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, United States of America.
Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Pediatric Nephrology, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Department of Genetics, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
BIOSS Center for Biological Signalling Studies and Center for Systems Biology (ZBSA), Albert-Ludwigs-University, Freiburg, Germany.
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL, United States of America.
GeneDx, Inc, Gaithersburg, MD, United States of America.
Sorbonne Université, UPMC, GRC ConCer-LD and AP-HP, Hôpital Trousseau, Service de Neuropédiatrie-Pathologie du développement, Paris, France.
Centre de référence des déficits intellectuels de causes rares, Inserm U 1141, Paris, France.
Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moèlle Épinière (ICM), Paris, France.
AP-HP, GH Pitié-Salpêtrière, Department of Genetics, Unit of Developmental Genomics, Paris, France.
AP-HP, Hôpital Trousseau, Centre de référence des malformations et maladies congénitales du cervelet, Département de génétique et embryologie médicale, Paris, France.


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.

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