This report describes an inherited syndromic disease postulated to be caused by more than one pathogenic mutation: one in the ADD3 gene and a second in the KAT2B gene. Comparing to patients with ADD3 mutational lesions only (see FBhh0000647), additional renal and cardiac phenotypes were postulated to be due to KAT2B dysfunction. The KAT2B protein functions as a histone acetyltransferase to promote transcriptional activation. There is a single orthologous gene in Drosophila, Gcn5, for which multiple genetic reagents, including classical loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis, have been generated. Dmel\Gcn5 is orthologous to a second gene in human, KAT2A.
UAS-wild-type constructs of human Hsap\KAT2B and Hsap\KAT2A have been introduced into flies. Expression of human KAT2A and KAT2B, either alone or in combination, fails to rescue the lethal phenotype of an amorphic mutation of Dmel\Gcn5.
Animals hemizygous for an amorphic mutation of Dmel\Gcn5 die during late larval or early pupal stages. Animals with reduced levels of Dmel\Gcn5 exhibit mild cardiac dysfunction and renal defects. When expressed ubiquitously, overexpression of wild-type Gcn5 rescues the lethal phenotype. A Dmel\Gcn5 gene carrying a mutational lesion analogous to the KAT2B variant implicated in this disease effects only partial rescue, suggesting that the variant is a hypomorphic mutation. See the 'Disease-Implicated Variants' table below.
Based on genetic interactions of Gcn5 and hts (the fly ortholog of ADD3), it is postulated that the two genes synergistically affect renal function in this disease.
[updated Apr. 2024 by FlyBase; FBrf0222196]
Six individuals in three families with intellectual disability and varying degrees of microcephaly were studied. Individuals from family A and B also shared bilateral cataracts, corpus callosum defects as well as specific skeletal defects such as shortening of the third and fourth metatarsals; the affected boy from family C suffered from epilepsy, severe speech delay and suspected cerebral palsy. Individuals in family A also exhibited cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS). (Goncalves et al., 2018, pubmed:29768408; FBrf0239084).
Homozygous or compound heterozygous mutations in the ADD3 gene were detected in each of the affected individuals. In individuals from family A, a homozygous missense mutation in the KAT2B gene was also detected (Goncalves et al., 2018, pubmed:29768408; FBrf0239084).
ADD3 encodes an adducin gamma subunit; it is a membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and plays a role in actin filament capping. [Gene Cards, ADD3; 2018.12.18]
The KAT2B protein functions as a histone acetyltransferase (HAT) to promote transcriptional activation; has significant histone acetyltransferase activity with core histones (H3 and H4) and with nucleosome core particles, as well as with some non-histone proteins. [Gene Cards, KAT2B; 2018.12.18]
Many to one: 3 human to 1 Drosophila. The 3 human genes are ADD3, ADD1, and ADD2.
Many to one: 2 human to 1 Drosophila; the second human gene is KAT2A.
High-scoring ortholog of human KAT2B and KAT2A (1 Drosophila to 2 human). Dmel\Gcn5 shares 46-48% identity and 64-66% similarity with the human genes.
High-scoring ortholog of human ADD3, ADD1, and ADD2 (1 Drosophila to 3 human). Dmel\hts shares 33-35% identity and 49-53% similarity with the human genes.
