This report describes the neurodevelopmental disorder Harel-Yoon syndrome (HAYOS); HAYOS usually exhibits autosomal dominant inheritance. Based on WES (whole-exome sequencing) analysis, it has been postulated that the human gene implicated in this disease is ATAD3A (ATPase Family, AAA Domain Containing 3A); ATAD3A encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. Results of analyses in Drosophila support the association of the ATAD3A gene with this syndrome. There is a single orthologous gene in Drosophila, bor, for which RNAi-targeting constructs, an allele caused by insertional mutagenesis, and a disease-implicated variant have been generated. Dmel\bor is also orthologous to two additional genes in human, ATAD3B and ATAD3C.
The human ATAD3A gene has not been introduced into flies.
Based on WES analysis, a recurrent de novo missense mutation in the ATAD3A gene was found in unrelated individuals suffering from a similar neurodevelopmental disorder. The analogous mutation was introduced into the orthologous fly gene; overexpression of the wild-type gene and the disease variant were compared. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R534W in the fly bor gene (corresponds to R528W in the human ATAD3A gene).
Ubiquitous or pan-neuronal overexpression of borR534W, the Drosophila mutation analogous to the human R528W variant, is lethal, unlike the result for overexpression of the wild-type gene. Cellular phenotypes resulting from overexpression of borR534W include a significant decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. These results support the hypothesis that the R528W pathological variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content.
Pan-neuronal expression of RNAi directed against Dmel\bor results in lethality at the larval or pupal stage. Overexpression of wild-type bor does not affect viability, although an expansion of mitochondrial size is observed. Many physical interactions have been described for Dmel\bor; see below and in the bor gene report.
For fly transgenic constructs and classical alleles, detailed phenotypic descriptions can be found in the allele reports; allele reports can be accessed from the gene report or by clicking on the allele symbols in the Disease Ontology and Reagent tables below.
[updated Sep. 2017 by FlyBase; FBrf0222196]
[HAREL-YOON SYNDROME; HAYOS](https://omim.org/entry/617183)
[ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3A; ATAD3A](https://omim.org/entry/612316)
Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. [from MIM:617183; 2017.09.18]
Harel-Yoon syndrome (HAYOS) is caused by heterozygous mutation in the ATAD3A gene; one family with autosomal recessive inheritance has been reported. [from MIM:617183; 2017.09.18]
ATAD3A encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. [Gene Cards, ATAD3A; 2017.09.19]
ATAD3A and ATAD3B are mitochondrial membrane proteins that contribute to the stabilization of large mitochondrial DNA (mtDNA)-protein complexes called nucleoids (He et al., 2007; pubmed:17210950). [from MIM:612316; 2017.09.18]
Many to one: 3 human to 1 Drosophila; the human genes are ATAD3A, ATAD3B, and ATAD3C.
Medium- to high-scoring ortholog of human ATAD3A, ATAD3B, and ATAD3C (1 Drosophila to 3 human). Dmel\bor shares 55-57% identity and 69-70% similarity with the human ATAD3A and ATAD3B genes.
