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Homozygous variant in ARL3 causes autosomal recessive cone rod dystrophy

Lookup NU author(s): Professor David SteelORCiD, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Copyright 2019 The AuthorsPURPOSE. 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.

Publication metadata

Author(s): Sheikh SA, Sisk RA, Schiavon CR, Waryah YM, Usmani MA, Steel DH, Sayer JA, Narsani AK, Hufnagel RB, Riazuddin S, Kahn RA, Waryah AM, Ahmed ZM

Publication type: Article

Publication status: Published

Journal: Investigative Ophthalmology and Visual Science

Year: 2019

Volume: 60

Issue: 14

Pages: 4811-4819

Online publication date: 01/11/2019

Acceptance date: 15/10/2019

Date deposited: 02/12/2019

ISSN (print): 0146-0404

ISSN (electronic): 1552-5783

Publisher: Association for Research in Vision and Ophthalmology Inc.


DOI: 10.1167/iovs.19-27263

PubMed id: 31743939


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Funder referenceFunder name
Kidney Research UK
Northern Counties Kidney Research Fund