GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism

RESEARCH ARTICLE GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism Alejandra Young 1,2 , Uma Dandekar 4 , Calvin Pan 4 , Avery Sader 1 , Jie J. Zheng 1 , Richard A. Lewis 5 , Debora B. Farber 1,2,3 * 1 Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America, 2 Molecular Biology Institute, UCLA, Los Angeles, CA, United States of America, 3 Brain Research Institute, UCLA, Los Angeles, CA, United States of America, 4 UCLA- GenoSeq Core, UCLA, Los Angeles, CA, United States of America, 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America a11111 * farber@jsei.ucla.edu Abstract OPEN ACCESS Citation: Young A, Dandekar U, Pan C, Sader A, Zheng JJ, Lewis RA, et al. (2016) GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism. PLoS ONE 11(9): e0162273. doi:10.1371/ journal.pone.0162273 Editor: Alfred S Lewin, University of Florida, UNITED STATES Received: July 14, 2016 Accepted: August 21, 2016 Published: September 8, 2016 Copyright: © 2016 Young et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data from this study have been submitted to the NCBI Sequence Read Archive (SRA) with accession # SRP074333. Funding: This work was funded by The Vision of Children Foundation, http://www.visionofchildren.org/ (AY). Stein Eye Institute core facilities used (available to DBF) were supported by an NIH Core center grant (EY000331) and by a grant from Research to Prevent Blindness. RAL received partial support from the Genetic Resource Association of Texas (GReAT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ocular albinism type 1 (OA), caused by mutations in the OA1 gene, encodes a G-protein coupled receptor, OA1, localized in melanosomal membranes of the retinal pigment epithe- lium (RPE). This disorder is characterized by both RPE macro-melanosomes and abnormal decussation of ganglion cell axons at the brain’s optic chiasm. We demonstrated previously that Oa1 specifically activates Gαi3, which also signals in the Oa1 transduction pathway that regulates melanosomal biogenesis. In this study, we screened the human Gαi3 gene, GNAI3, in DNA samples from 26 patients who had all clinical characteristics of OA but in whom a specific mutation in the OA1 gene had not been found, and in 6 normal control indi- viduals. Using the Agilent HaloPlex Target Enrichment System and next-generation sequencing (NGS) on the Illumina MiSeq platform, we identified 518 variants after rigorous filtering. Many of these variants were corroborated by Sanger sequencing. Overall, 98.8% coverage of the GNAI3 gene was obtained by the HaloPlex amplicons. Of all variants, 6 non-synonymous and 3 synonymous were in exons, 41 in a non-coding exon embedded in the 3’ untranslated region (UTR), 6 in the 5’ UTR, and 462 in introns. These variants included novel SNVs, insertions, deletions, and a frameshift mutation. All were found in at least one patient but none in control samples. Using computational methods, we modeled the GNAI3 protein and its non-synonymous exonic mutations and determined that several of these may be the cause of disease in the patients studied. Thus, we have identified GNAI3 as a second gene possibly responsible for X-linked ocular albinism. Introduction X-linked ocular albinism type 1, historically called the Nettleship-Falls type, has been viewed as the most common form of ocular albinism. It has an estimated prevalence of 1 in every 50,000 live births in the USA. This disorder occurs almost exclusively in males and is characterized by early onset nystagmus, iris transillumination, blond or relatively hypopigmented fundus color, congenital hypoplasia of the fovea centralis, and reduced visual acuity. On careful comparison, PLOS ONE | DOI:10.1371/journal.pone.0162273 September 8, 2016