RESUMEN
MYOC encodes a secretary glycoprotein of 504 amino acids named myocilin. MYOC is the first gene to be linked to juvenile open-angle glaucoma (JOAG) and some forms of adult-onset primary open-angle glaucoma (POAG). The gene was identified as an up-regulated molecule in cultured trabecular meshwork (TM) cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (TIGR). Elevated intraocular pressure (IOP), due to decreased aqueous outflow, is the strongest known risk factor for POAG. Increasing evidence showed that the modulation of the wild-type (wt) myocilin protein expression is not causative of glaucoma while some misfolded and self-assembly aggregates of mutated myocilin may be associated with POAG in related or unrelated populations. The etiology of the disease remains unclear. Consequently, a better understanding of the molecular mechanisms underlying POAG is required to obtain early diagnosis, avoid potential disease progression, and develop new therapeutic strategies. In the present study, we review and discuss the most relevant studies regarding structural characterizations, expressions, molecular interactions, putative functions of MYOC gene and/or its corresponding protein in POAG etiology.
Asunto(s)
Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/metabolismo , Proteínas del Ojo/química , Proteínas del Ojo/metabolismo , Glaucoma de Ángulo Abierto/metabolismo , Glicoproteínas/química , Glicoproteínas/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas del Citoesqueleto/genética , Proteínas del Ojo/genética , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Humanos , Datos de Secuencia Molecular , Pliegue de Proteína , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: The purpose of this study was to screen juvenile open angle glaucoma (JOAG) patients from Brazil for variants within the MYOC and CYP1B1 genes. MATERIAL AND METHODS: In this study, we evaluated the coding regions of MYOC and CYP1B1 genes in 100 non-related patients with JOAG and 200 controls through Sanger sequencing. We also tested the most frequent single nucleotide variants of CYP1B1 for association with JOAG. RESULTS: Sixteen different sequence variants in the MYOC gene were observed in JOAG patients: eight variants were described as neutral and eight were identified in 34 out of 100 patients with JOAG and no controls, thus being considered damaging. In the CYP1B1 gene, nine neutral variants and two damaging alterations were found among JOAG patients. No association between CYP1B1 variants and JOAG was detected. CONCLUSION: While MYOC damaging alterations were highly prevalent (34%), CYP1B1 damaging variants were less frequent (2%) in this cohort of Brazilian JOAG patients.
Asunto(s)
Citocromo P-450 CYP1B1/genética , Proteínas del Citoesqueleto/genética , Proteínas del Ojo/genética , Variación Genética , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Adulto , Brasil/epidemiología , Estudios de Cohortes , Exones/genética , Femenino , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/epidemiología , Gonioscopía , Humanos , Presión Intraocular , Masculino , Mutación , Reacción en Cadena en Tiempo Real de la Polimerasa , Agudeza VisualRESUMEN
Mutations in the myocilin gene (MYOC) account for most cases of autosomal dominant juvenile-onset open-angle glaucoma (JOAG), an earlier and more severe form of POAG. We accessed seven members of a Brazilian JOAG family by clinical and molecular investigation. Four out of seven family members were diagnosed with JOAG. All of these patients presented high intraocular pressure and two of them were bilaterally blind. The disease onset varied from 20 to 30years old. There was a nine-year-old family member who had not yet manifested the disease, although he was also a carrier of the mutation. Ophthalmologic examination included: evaluation of the visual field and optic disc, intraocular pressure measurement, and gonioscopy. The three exons and intron/exon junctions of the MYOC gene were screened for mutations through direct sequencing of PCR-amplified DNA fragments. Mutation screening revealed an in-frame mutation in the third exon of the MYOC gene: an insertion of six nucleotides between the cDNA positions 1187 and 1188 (c.1187_1188insCCCAGA, p.D395_E396insDP). This mutation presented an autosomal dominant pattern of inheritance, segregating with the disease in four family members for three generations, and it was absent in 60 normal controls. We also performed a computational structure modeling of olfactomedin-like domain of myocilin protein and conducted in silico analysis to predict the structural changes in the myocilin protein due to the presence of the mutation. These findings may be important for future diagnosis of other presymptomatic family members, as well as for the increase of the panel of MYOC mutations and their effects on phenotype.