Homozygous variant in ARL3 causes autosomal recessive cone rod dystrophy
JournalInvestigative Ophthalmology and Visual Science
PublisherAssociation for Research in Vision and Ophthalmology Inc.
MetadataShow full item record
AbstractPurpose: 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. Copyright 2019 The Authors
SponsorsThis study was also supported by National Institutes of Health: National Institute on Deafness and Other Communication Disorders Grant R01DC016295 (to ZMA) and National Institute of General Medical Sciences Grant R35GM122568 (to RAK and CS). JAS is funded by Kidney Research UK and the Northern Counties Kidney Research Fund.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85075284874&doi=10.1167%2fiovs.19-27263&partnerID=40&md5=849e1fdec1f59da5216e21d418082ec9; http://hdl.handle.net/10713/11481