This report describes developmental and epileptic encephalopathy (postulated), ROBO1-related. The human gene implicated in this disease is ROBO1, an axon guidance receptor that defines a novel subfamily of immunoglobulin superfamily proteins that is highly conserved from fruit flies to mammals. There are three orthologous genes in Drosophila, Dmel\robo1, Dmel\robo2, and Dmel\robo3, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human gene Hsap\ROBO1 have been introduced into flies, including wild-type ROBO1 and a gene carrying a mutational lesion implicated in a second distinct disease (see the Human Disease Model report 'nystagmus 8, congenital, autosomal recessive' FBhh0001474).
Amorphic and loss-of-function mutations of Dmel\robo1 are lethal; embryonic phenotypes exhibit axon pathfinding defects, with axons ectopically crossing the the ventral nerve cord midline. A mutation analogous to a dominant human variant implicated in this disease has been introduced into the fly gene; results in flies suggest that it is a neomorphic allele. See the 'Disease-Implicated Variants' table below.
[updated Oct. 2024 by FlyBase; FBrf0222196]
A single affected male exhibited severe early-onset epileptic encephalopathy, including infantile spasms with loss of conciousness observed at three months of age, along with delays in developmental milestones. An electroencephalogram (EEG) showed a large number of high-amplitude sharp waves, spikes, irregular slow waves firing in bilateral central, parietal and mid-posterior temporal regions during both awake and asleep states. (Huang et al., 2022; pubmed:35348658; FBrf0254345).
This form of developmental and epileptic encephalopathy is caused by heterozygous mutation in the ROBO1 gene (Huang et al., 2022; pubmed:35348658; FBrf0254345).
The protein encoded by ROBO1 is a member of the immunoglobulin gene superfamily and encodes an integral membrane protein that functions in axon guidance and neuronal precursor cell migration. This receptor is activated by SLIT-family proteins, resulting in a repulsive effect on glioma cell guidance in the developing brain. [ Entrez:6091 ; 2022.09.22]
Many to many: multiple related genes in both species.
High-scoring ortholog of human ROBO2 moderate-scoring ortholog of human ROBO1 and ROBO3 (many Drosophila to many human).
