Homozygous Variant in ARL3 Causes Autosomal Recessive Cone Rod Dystrophy

• Authors: Shakeel A. Sheikh, University of Maryland; Robert A. Sisk, Cincinnati Childrens Hospital Medical Center; Cara R. Schiavon, Emory University; Yar M. Waryah, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan; Muhammad A. Usmani, University of Maryland; David H. Steel, Newcastle University; John A. Sayer, Newcastle University; Ashok K. Narsani, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan; Robert B. Hufnagel, National Institutes of Health; Saima Riazuddin, University of Maryland; Richard Kahn, Emory University; Ali M. Waryah, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan; Zubair M. Ahmed, University of Maryland
• Journal Title: Investigative Ophthalmology & Visual Science
• Volume: Volume 60, Number 14
• Publisher: AVRO Publishing | 2019-11-01, Pages 4811-4819
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1167/iovs.19-27263
• Subjects: Biology, Genetics; Health Sciences, Opthamology; Biology, Molecular; Chemistry, Biochemistry; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Ophthalmology; ARL3; cone rod dystrophy; retinitis pigmentosa; autosomal recessive; Retinal degeneration; Trafficking; Mutations; GTPASE; RP2; Proteins; Genes

Abstract

PURPOSE: Cone rod dystrophy (CRD) is a group of inherited retinopathies characterized by the loss of cone and rod photoreceptor cells, which results in poor vision. This study aims to clinically and genetically characterize the segregating CRD phenotype in two large, consanguineous Pakistani families. METHODS: Funduscopy, optical coherence tomography (OCT), electroretinography (ERG), color vision, and visual acuity assessments were performed to evaluate the retinal structure and function of the affected individuals. Exome sequencing was performed to identify the genetic cause of CRD. Furthermore, the mutation’s effect was evaluated using purified, bacterially expressed ADP-ribosylation factor-like protein 3 (ARL3) and mammalian cells. RESULTS: Fundus photography and OCT imaging demonstrated features that were consistent with CRD, including bull’s eye macular lesions, macular atrophy, and central photoreceptor thinning. ERG analysis demonstrated moderate to severe reduction primarily of photopic responses in all affected individuals, and scotopic responses show reduction in two affected individuals. The exome sequencing revealed a novel homozygous variant (c.296G>T) in ARL3, which is predicted to substitute an evolutionarily conserved arginine with isoleucine within the encoded protein GTP-binding domain (R99I). The functional studies on the bacterial and heterologous mammalian cells revealed that the arginine at position 99 is essential for the stability of ARL3. CONCLUSIONS: Our study uncovers an additional CRD gene and assigns the CRD phenotype to a variant of ARL3. The results imply that cargo transportation in photoreceptors as mediated by the ARL3 pathway is essential for cone and rod cell survival and vision in humans.