RESUMEN
How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs' endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CTG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at one-two copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because: (i) Affected tissue is routinely removed during surgery; (ii) The expanded CTG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and (iii) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here, we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cells. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in pre-symptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease.
Asunto(s)
Distrofia Endotelial de Fuchs/genética , Factor de Transcripción 4/genética , Expansión de Repetición de Trinucleótido/genética , Repeticiones de Trinucleótidos/genética , Adulto , Anciano , Biomarcadores/metabolismo , Córnea/metabolismo , Córnea/patología , Femenino , Distrofia Endotelial de Fuchs/patología , Distrofia Endotelial de Fuchs/terapia , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Especificidad de Órganos/genética , Análisis de Secuencia de ARNRESUMEN
PURPOSE: To describe 2 cases of congenital corneal endothelial edema resulting from novel de novo mutations. METHODS: Case A patient was a 15-month-old white child and case B patient was a 3-year-old Hispanic child presenting with bilateral cloudy corneas since birth. Clinicopathologic findings are presented. DNA samples were screened for mutations in candidate genes by Sanger sequencing. RESULTS: Slit-lamp examination of case A patient revealed stromal edema and haze. Histology of the keratoplasty button showed stromal thickening with loss of endothelium and thin Descemet membrane. Sanger sequencing established the diagnosis of congenital hereditary endothelial dystrophy by detection of a compound heterozygous mutation in SLC4A11. The proband displayed a novel de novo frameshift mutation in one SLC4A11 allele, p.(Pro817Argfs*32), in conjunction with a maternally inherited missense mutation in SLC4A11, p.(Arg869His). Case B patient similarly presented with stromal edema and stromal haze. Histopathologic analysis revealed a spongy epithelium, focal discontinuities in Bowman layer, stromal thickening with areas of compacted posterior stroma, variable thickness of Descemet membrane, and regional multilayered endothelium. Sanger sequencing found a novel de novo nonsense mutation in the first exon of ZEB1, p.(Cys7*). CONCLUSIONS: To the authors' knowledge, we report the earliest clinical presentation of posterior polymorphous corneal dystrophy resulting from a de novo mutation in ZEB1. Additionally, we present a congenital hereditary endothelial dystrophy case with a thin Descemet membrane with a novel compound heterozygous SLC4A11 mutation. In the absence of a family history or consanguinity, de novo mutations may result in congenital corneal endothelial dystrophies.
Asunto(s)
Proteínas de Transporte de Anión/genética , Antiportadores/genética , Distrofias Hereditarias de la Córnea/genética , Edema Corneal/genética , Mutación del Sistema de Lectura , Proteínas de Homeodominio/genética , Mutación Missense , Factores de Transcripción/genética , Preescolar , Distrofias Hereditarias de la Córnea/diagnóstico , Distrofias Hereditarias de la Córnea/cirugía , Edema Corneal/diagnóstico , Edema Corneal/cirugía , Análisis Mutacional de ADN , Humanos , Lactante , Queratoplastia Penetrante , Reacción en Cadena de la Polimerasa , Agudeza Visual , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Ophthalmomyiasis externa is an uncommon condition in North America. If not recognized and managed accordingly, it can be complicated by the potentially fatal condition ophthalmomyiasis interna. Ophthalmomyiasis externa is mainly caused by the sheep bot fly Oestrus ovis; thus, it is more common in farming communities. We report a case of ophthalmomyiasis externa in a young woman from Dallas County, Texas, who had no known history of contact with farm animals.
