Abstract
Purpose :
ARL3 (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa or autosomal recessive Joubert syndrome. A recent report showed a homozygous variant in ARL3 caused cone-rod dystrophy. We found a family with rod-cone dystrophy and confirmed it was associated with compound heterozygous variants in ARL3 gene.
Methods :
Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed in the18-year-old male proband and the family members. DNA was extracted from peripheral blood. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel containing genes associated with inherited retinal diseases. Sanger sequencing and co-segregation were conducted in the family members. The pathogenic prediction was performed with ACMG guideline. Changes of protein structure mediated by the variants were studied in vitro. ARL3 protein stability and its interaction with RP2 protein were assessed by cycloheximide chase assay and co-immunoprecipitation (Co-IP) assay.
Results :
Visual acuity of the proband was 0.25 in the right and 0.20 in the left eye, while his mother and sister was normal. Fundus photography showed peripheral bone spicule pigmentation and ERG revealed severe reduction in scotopic responses and to less extent in photopic responses bilaterally. The proband also had tunnel visual field and dyserythrochloropsia. But he did not have hearing abnormality, mental dysplasia or gait instability. Targeted NGS identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in ARL3. Bioinformatics analysis indicated that the amino acid positions of the two variants are highly conserved among species. LRT, Mutation Taster, SIFT, FATHMM and CADD predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. According to the ACMG guidelines, the two variants were likely pathogenic, supported by evidences: PS2, PM1, PM2, PP1 and PP3. In addition, the ARL3 mutations destabilized ARL3 protein, and disrupted the interaction between ARL3 and RP2 in HEK293T cells.
Conclusions :
We showed two novel compound heterozygous variants in ARL3 were associated with autosomal recessive rod-cone dystrophy. The two variants in ARL3 could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.
This is a 2021 ARVO Annual Meeting abstract.