Homozygous Variant in<i>ARL3</i>Causes Autosomal Recessive Cone Rod Dystrophy

Sheikh, Shakeel A.; Sisk, Robert A.; Schiavon, Cara R.; Waryah, Yar Muhammad; Usmani, Muhammad A.; Steel, David; Sayer, John A.; Narsani, Ashok Kumar; Hufnagel, Robert B.; Riazuddin, Saima; Kahn, Richard; Waryah, Ali Muhammad; Ahmed, Zubair M.

doi:10.1167/iovs.19-27263

Cited by 12 publications

(16 citation statements)

References 29 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glutamylation of the RPGR ORF15 as posttranslational modification is critical for its function in photoreceptors [ 76 ]. ARL3 (ADP-ribosylation factor-like protein 3), a small G protein, is mainly situated on the connecting cilium myoid region of the inner segments of cone photoreceptors and acts as an allosteric factor for the release of lipidated proteins bound to PDE6δ (δ unit of cGMP phosphodiesterase) [ 86 ]. Loss of ARL3 function may impair the trafficking of the lipidated outer segment proteins, leading to outer segment shortening and slow retinal degeneration [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, missense variants in ARL3 were reported to cause Joubert syndrome, characterized by hypoplasia of the cerebellar vermis, developmental delay, renal anomalies, and rod-cone dystrophy [ 88 ]. However, in a recent study, a novel missense variant p.(Arg99Ile) in ARL3 has been described, resulting in a cone-rod dystrophy [ 86 ]. CEP290 (NPHP6) is primarily involved in syndromic and non-syndromic LCA [ 89 ], however, a rare form of cone-dominated retinal dystrophy associated with mutations in CEP290 has recently been described in two siblings [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Hadalin

Šuštar

Volk

et al. 2021

Genes

View full text Add to dashboard Cite

Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant’s putative impact, and predicted pathogenicity; and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462–6342 μm). Follow up after 2–11 years showed enlargement of the diameter (avg. 100 μm/year). The novel c.3457T>A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Hadalin

Šuštar

Volk

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…Homozygous mutation in ARL3 was identified as a cause of autosomal recessive Joubert syndrome, a neurodevelopmental disorder that may include retinal dystrophy, in two unrelated families (Alkanderi et al, 2018). A role for ARL3 in non-syndromic autosomal recessive IRDs has also been reported (Sheikh et al, 2019;Fu et al, 2021). Two consanguineous Pakistani families with common ancestry both had affected members with a homozygous c.296 > T (p.Arg99Ile) variant (Sheikh et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the c.269A > G (p.Tyr90Cys) variant was determined to be a de novo mutation in two unrelated families, each with two generations of affected members (Strom et al, 2016;Holtan et al, 2019). ARL3 has also been implicated as an autosomal recessive cause of Joubert syndrome and non-syndromic retinal degeneration (Alkanderi et al, 2018;Sheikh et al, 2019;Fu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

Ratnapriya

Jacobson

Cideciyan

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.

show abstract

“…In addition, homozygocity for two different ARL3 Arg149 missense variants (c.445C>T, p.Arg149Cys; c.446G>A, p.Arg149His) were reported to cause Joubert syndrome (Alkanderi et al, 2018 ). A most recent report indicated that a homozygous variant in ARL3 (c.296G>T, p. Arg99Ile) caused cone-rod dystrophy (CRD) in two consanguineous families (Sheikh et al, 2019 ). In this study, we found a Chinese family with typical rod-cone dystrophy (RCD), which was associated with novel compound heterozygous variants in ARL3 .…”

Section: Introductionmentioning

confidence: 99%

Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene

Yao

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Purpose:ARL3 (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa (RP) or autosomal recessive Joubert syndrome. We found a family with rod-cone dystrophy (RCD) and verified it was associated with compound heterozygous variants in ARL3 gene.Methods: Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel. Sanger sequencing and co-segregation were conducted in the family members. 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 18-year-old male proband was 0.25 in the right and 0.20 in the left eye, while his non-consanguineous parents and sister was normal. The proband showed signs of RCD, including nyctalopia, peripheral field loss, bone-spicule deposits in the retina, and reduced ERG responses. The father, aged 50 years old, showed visual acuity of 1.0 in both eyes. Unlike the proband, he presented late onset and mild cone-rod dystrophy (CRD), including macular atrophy, central scotomata, moderate reduction in photopic ERG responses. None of all the family members had hearing abnormality, mental dysplasia or gait instability. We identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in ARL3 in the proband, while his father only had variant c.91A>G. Bioinformatics analysis indicated amino acid positions of the two variants are highly conserved among species. The in silico tools predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. Based on the ACMG guidelines, the two variants were likely pathogenic. In addition, the ARL3 mutations destabilized ARL3 protein, and the mutation c.353G>T disrupted the interaction between ARL3 and RP2 in HEK293T cells.Conclusions: We showed novel compound heterozygous variants in ARL3 were associated with early onset of autosomal recessive RCD, while c.91A>G along may be associated with a late onset of dominant CRD. The two variants in ARL3 could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.

show abstract

Homozygous Variant inARL3Causes Autosomal Recessive Cone Rod Dystrophy

Cited by 12 publications

References 29 publications

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene

Contact Info

Product

Resources

About