GNAI3: Another Candidate Gene to Screen in Persons with Ocular Albinism.
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 epithelium (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 individuals. 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.
Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America.|Molecular Biology Institute, UCLA, Los Angeles, CA, United States of America.
Alejandra
A
Young
UCLA-GenoSeq Core, UCLA, Los Angeles, CA, United States of America.
Uma
http://orcid.org/0000-0001-6456-8349
U
Dandekar
UCLA-GenoSeq Core, UCLA, Los Angeles, CA, United States of America.
Calvin
http://orcid.org/0000-0002-0752-833X
C
Pan
Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America.
Avery
A
Sader
Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America.
Jie J
http://orcid.org/0000-0001-6524-6800
JJ
Zheng
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America.
Richard A
http://orcid.org/0000-0002-6644-6385
RA
Lewis
Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States of America.|Molecular Biology Institute, UCLA, Los Angeles, CA, United States of America.|Brain Research Institute, UCLA, Los Angeles, CA, United States of America.
Debora B
DB
Farber
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D016117:Albinism, Ocular / Q000175:diagnosis / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000235:genetics*; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go