RESUMEN
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.
Asunto(s)
Albinismo Ocular/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Regiones no Traducidas 3'/genética , Regiones no Traducidas 5'/genética , Albinismo Ocular/diagnóstico , Emparejamiento Base/genética , Secuencia de Bases , Exones/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/química , Sitios Genéticos , Heterocigoto , Homocigoto , Humanos , Intrones/genética , Modelos Moleculares , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: To examine the potential contribution of the serotonin hydroxylase (TPH1 and TPH2) genes, and the serotonin transporter promoter polymorphism (5HTTLPR) to the unique and pleiotropic risk of PTSD symptoms and depressive symptoms. METHODS: Participants included 200 adults exposed to the 1988 Spitak earthquake from 12 multigenerational families (3 to 5 generations). Severity of trauma exposure, PTSD, and depressive symptoms were assessed using standard psychometric instruments. Pedigree-based variance component analysis was used to assess the association between select genes and the phenotypes. RESULTS: After adjusting for age, sex, exposure and environmental variables, there was a significant association of PTSD symptoms with the 't' allele of TPH1 SNP rs2108977 (p<0.004), explaining 3% of the phenotypic variance. This allele also showed a non-significant trend for an association with depressive symptoms (p=0.08). Also, there was a significant association of PTSD symptoms and the 't' allele of TPH2 SNP rs11178997 (p=0.03), explaining 4% of the variance. Depressive symptoms were significantly associated with the 's' allele of 5HTTLPR (p=0.03), explaining 4% of the variance. LIMITATIONS: Retrospective rating of exposure may have been subject to memory failure leading to misestimation of symptom severities. Second, findings may not be generalizable to other ethnic/racial populations. CONCLUSION: To our knowledge, this is the first published report showing that variants in TPH1 and TPH2 genes constitute risk factors for PTSD symptoms. Additionally, the TPH1 gene may be associated pleiotropically with PTSD and depressive symptoms. The association of the 's' allele of 5HTTLPR polymorphism with depression adds to similar findings from case/case-control studies.
