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

PLoS Genetics
Sara GonçalvesMatias Simons

Abstract

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 a...Continue Reading

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Citations

Aug 24, 2019·Journal of Medical Genetics·Laurence HubertClaude Besmond
Mar 27, 2019·Journal of the American Society of Nephrology : JASN·Zvonimir Marelja, Matias Simons
May 16, 2019·Disease Models & Mechanisms·Mireia Coll-TanéAnnette Schenck
Feb 8, 2020·Journal of the American Society of Nephrology : JASN·Fan FanRichard J Roman
Jan 15, 2021·Clinical Science·Md Ezazul HaqueDong-Kug Choi
Aug 9, 2020·Aging and Disease·Asish K Ghosh

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Methods Mentioned

BETA
biopsy
exome sequencing
acetylate
transgenic
acetylation
histone acetylation
biopsies
transfection
PCR

Software Mentioned

GeneMatcher
Image J
PolyPhen
Optical Heartbeat Analysis
gnomAD browser
bcl2fastq Conversion
Lifescope
gnomAD

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