RESUMEN
Purpose: Age-related macular degeneration (AMD) is a leading cause of vision loss. A Previous study based on the co-localization analysis of the genome-wide association study (GWAS) and eQTL genetic signals have reported that single nucleotide polymorphisms (SNPs), including rs760975, rs11528744, rs3761159, rs7212510, rs6965458, rs7559693, rs56108400, rs28495773, rs9928736, rs11777697, rs4381465 are associated with AMD in Americans. The aim of this study was to investigate the association of these SNPs in a Han Chinese population. Methods: There were 576 patients with wet AMD and 572 healthy controls collected in this study. All SNPs were genotyped by flight mass spectrum. Hardy-Weinberg equilibrium was applied to evaluate allele distributions for both AMD and control groups. The genotype and allele frequencies were evaluated using the χ2 tests. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for the risk of genotype and allele. Results: Three of the 11 SNPs (rs11528744 in HTRA1, rs9928736 in BCRA1 and rs4381465 in B3GLCT) were found to be significantly associated with AMD in the allelic model (corrected p = 0.001, OR = 1.391, 95%CI = 1.179-1.640 for rs11528744; corrected p = 0.004, OR = 0.695, 95%CI = 0.544-0.888 for rs9928736; corrected p = 0.002, OR = 0.614, 95%CI = 0.448-0.841 for rs4381465). There were no differences for the remaining eight SNPs between AMD cases and healthy controls. Conclusion: Our results showed that HTRA1 rs11528744, BCRA1 rs9928736, and B3GLCT rs4381465 were associated with wet AMD, suggesting that HTRA1, BCRA1, and B3GLCT genes may be involved in the development of AMD.
RESUMEN
Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.
Asunto(s)
Opacidad de la Córnea , Anomalías del Ojo , Segmento Anterior del Ojo/anomalías , Hibridación Genómica Comparativa , Opacidad de la Córnea/diagnóstico , Opacidad de la Córnea/genética , Opacidad de la Córnea/patología , Variaciones en el Número de Copia de ADN/genética , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Humanos , Mutación/genética , Factores de Transcripción SOXB1/genéticaRESUMEN
Peters Plus Syndrome (PTRPLS OMIM #261540) is a severe congenital disorder of glycosylation where patients have multiple structural anomalies, including Peters anomaly of the eye (anterior segment dysgenesis), disproportionate short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable additional abnormalities. PTRPLS patients and some Peters Plus-like (PTRPLS-like) patients (who only have a subset of PTRPLS phenotypes) have mutations in the gene encoding ß1,3-glucosyltransferase (B3GLCT). B3GLCT catalyzes the transfer of glucose to O-linked fucose on thrombospondin type-1 repeats. Most B3GLCT substrate proteins belong to the ADAMTS superfamily and play critical roles in extracellular matrix. We sought to determine whether the PTRPLS or PTRPLS-like mutations abrogated B3GLCT activity. B3GLCT has two putative active sites, one in the N-terminal region and the other in the C-terminal glycosyltransferase domain. Using sequence analysis and in vitro activity assays, we demonstrated that the C-terminal domain catalyzes transfer of glucose to O-linked fucose. We also generated a homology model of B3GLCT and identified D421 as the catalytic base. PTRPLS and PTRPLS-like mutations were individually introduced into B3GLCT, and the mutated enzymes were evaluated using in vitro enzyme assays and cell-based functional assays. Our results demonstrated that PTRPLS mutations caused loss of B3GLCT enzymatic activity and/or significantly reduced protein stability. In contrast, B3GLCT with PTRPLS-like mutations retained enzymatic activity, although some showed a minor destabilizing effect. Overall, our data supports the hypothesis that loss of glucose from B3GLCT substrate proteins is responsible for the defects observed in PTRPLS patients, but not for those observed in PTRPLS-like patients.
Asunto(s)
Labio Leporino/enzimología , Labio Leporino/genética , Córnea/anomalías , Galactosiltransferasas/genética , Galactosiltransferasas/metabolismo , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Trastornos del Crecimiento/enzimología , Trastornos del Crecimiento/genética , Deformidades Congénitas de las Extremidades/enzimología , Deformidades Congénitas de las Extremidades/genética , Mutación/genética , Proteínas ADAMTS/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Biocatálisis , Córnea/enzimología , Estabilidad de Enzimas , Fucosa/metabolismo , Galactosiltransferasas/química , Glucosa/metabolismo , Glucosiltransferasas/química , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Dominios Proteicos , Secuencias Repetitivas de Aminoácido , Homología Estructural de ProteínaRESUMEN
Peters plus syndrome is a rare genetic condition wherein multiple systemic involvement with distinctive facial features are manifested, whilst the hallmark is Peters anomaly, occuring from anterior segment dysgenesis. Homozygous variants in the B3GLCT gene were identified to underlie this disorder. We here report on a onemonth- old female patient with typical features characteristic of Peters plus syndrome in whom a homozygous pathogenic mutation in the B3GLCT gene was detected.
Asunto(s)
Anomalías del Ojo , Deformidades Congénitas de las Extremidades , Labio Leporino , Córnea/anomalías , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Femenino , Galactosiltransferasas , Glucosiltransferasas , Trastornos del Crecimiento , Humanos , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/genéticaRESUMEN
BACKGROUND: Peters plus syndrome (PPS) is a combination of congenital Peters anomaly and systemic abnormalities. It is inherited most commonly in an autosomal recessive pattern with homozygous B3GLCT mutations. Ocular findings consist predominantly anterior segment abnormalities without posterior segment involvement. CASE PRESENTATION: In this presentation, we report a case of PPS with homozygous pathogenic variant in B3GLCT who presented with classic anterior segment findings, systemic abnormalities, as well as atypical bilateral chorioretinal atrophy. The chorioretinal findings were characterized with spectral-domain optical coherence tomography. CONCLUSIONS: Our report expands the phenotypic descriptions of PPS by characterizing posterior segment findings.