This report describes cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay, which shows autosomal recessive inheritance. The human gene implicated in this disease is OXR1. There is a single high-ranking ortholog of OXR1 in Drosophila, mtd, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical alleles have been generated.
The human gene Hsap\OXR1 has been introduced into flies.
Flies lacking mtd generally die during pupation, a phenotype which could be rescued by expression of mtd itself. mtd-null flies could also be homologously rescued (functionally complemented) by expressing a single region (the TLDc domain) from either of the two human mtd orthologs, Hsap\OXR1 and Hsap\NCOA7.
mtd-null escaper flies are bang-sensitive (a seizure phenotype) and show climbing defects. Knocking down mtd in neurons to a level that allows flies to survive for ~10-15 days results in neuronal loss and vacuolization. mtd RNAi knockdown flies also show aberrant accumulation of acidic veiscles, a sign of defective autophagy seen in primary fibroblasts from CHEGDD-affected individuals.
[updated Jan. 2020 by FlyBase; FBrf0222196]
[CEREBELLAR HYPOPLASIA/ATROPHY, EPILEPSY, AND GLOBAL DEVELOPMENTAL DELAY; CHEGDD](https://omim.org/entry/213000)
[OXIDATION RESISTANCE 1; OXR1](https://omim.org/entry/605609)
Bi-allelic truncating or splicing mutations in OXR1 cause a severe neurological disease with a history of developmental delay, intellectual disability, hypotonia, epilepsy, and cerebellar anomalies. (from Wang et al. 2019, FBrf0244183.)
Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of hypotonia and developmental delay with subsequent impaired intellectual development and severe speech delay. In childhood, affected individuals show delayed walking and develop epilepsy that is usually controlled by medication. Brain imaging shows cerebellar hypoplasia/atrophy (summary by Wang et al. 2019, FBrf0244183 / pubmed:31785787). [from MIM:213000, 2020.02.06]
In 5 patients from 3 unrelated families with CHEGDD, Wang et al. (FBrf0244183 / pubmed:31785787) identified homozygous or compound heterozygous loss-of-function mutations in the OXR1 gene (605609.0001-605609.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None of the variants were found in the gnomAD database. Patient-derived fibroblasts from families 2 and 3 showed undetectable OXR1 protein levels. [from MIM:213000, 2020.02.06]
Many to one: 2 human genes to 1 Drosophila gene.
Single, high-ranking ortholog of OXR1. mtd has orthology to both Hsap\OXR1 and Hsap\NCOA7.
