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Early onset or syndromic epilepsy v2.491 OXR1 Sarah Leigh Tag for-review was removed from gene: OXR1.
Early onset or syndromic epilepsy v2.491 OXR1 Sarah Leigh commented on gene: OXR1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.490 OXR1 Sarah Leigh Source Expert Review Green was added to OXR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Tag for-review tag was added to gene: OXR1.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.136 OXR1 Sarah Leigh Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Early onset or syndromic epilepsy v2.135 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Early onset or syndromic epilepsy v2.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787, 22028674; Phenotypes: Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay, MIM# 213000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.497 OXR1 Konstantinos Varvagiannis gene: OXR1 was added
gene: OXR1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum
Penetrance for gene: OXR1 were set to Complete
Review for gene: OXR1 was set to GREEN
Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature