RESUMEN
In optic neuritis (ON), transient thickening of the macular retinal nerve fibre layer (RNFL) can be observed. This optical coherence tomography-based observation is not understood. The axonal diameter correlates with the neurofilament (Nf) protein content, but there are no data on the retinal tissue concentration of Nfs. The myelin-oligodendrocyte-glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) model was used to investigate the retinas of Brown Norway rats with (i) visual evoked potentials (VEP) confirmed ON, (ii) VEP confirmed absence of ON and (iii) control animals. Twenty retinas were collected from MOG-EAE and control rats 27 days after immunisation. Retinal tissue Nf concentrations per total protein (µg/mg) were significantly higher in MOG-EAE rats with ON (median 4.29, interquartile range [IQR] 3.41-5.97) compared with MOG-EAE rats without ON (1.14, IQR 1.10-1.67) or control rats (0.93, IQR 0.45-4.00). The data suggest that up-regulation of Nf expression in the retinal ganglion cells precedes development of RNFL atrophy and plausibly explains the transient increase of axonal diameter and RNFL thickening.
Asunto(s)
Neoplasias Óseas/metabolismo , Calcáneo/diagnóstico por imagen , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Síndromes Paraneoplásicos Oculares/genética , Enfermedades de la Retina/genética , Adolescente , Biomarcadores de Tumor/metabolismo , Biopsia , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Imagen por Resonancia Magnética , Síndromes Paraneoplásicos Oculares/diagnóstico , Síndromes Paraneoplásicos Oculares/metabolismo , Glándula Pineal/metabolismo , ARN Neoplásico/genética , Retina/metabolismo , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/metabolismo , Factores de TiempoRESUMEN
OBJECTIVE: To characterize the clinical phenotype, with an emphasis on electrophysiologic findings, in a family with autosomal dominant retinitis pigmentosa caused by mutation in the recently identified KLHL7 gene. METHODS: Eleven patients from a single family were selected from the Swedish retinitis pigmentosa register. Four patients had been examined 13 to 17 years earlier and underwent further ophthalmologic examination, including visual acuity, fundus inspection, Goldmann perimetry, full-field electroretinography (ERG), multifocal ERG, and optical coherence tomography. KLHL7 mutation was identified by sequence analysis. RESULTS: In most examined family members, the fundus showed minor abnormalities. Full-field ERG demonstrated reduced cone and rod function, but rod responses were preserved in some patients late in life. Follow-up (
Asunto(s)
Autoantígenos/genética , Mutación , Retinitis Pigmentosa/genética , Adolescente , Adulto , Anciano , Electrorretinografía , Femenino , Genes Dominantes , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Sistema de Registros , Suecia , Tomografía de Coherencia Óptica , Agudeza Visual , Pruebas del Campo Visual , Campos Visuales , Adulto JovenRESUMEN
Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G-->A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
Asunto(s)
Autoantígenos/genética , Genes Dominantes , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , Retinitis Pigmentosa/genética , Secuencia de Aminoácidos , Autoantígenos/metabolismo , Cromosomas Humanos Par 7/genética , Ensayo de Inmunoadsorción Enzimática , Perfilación de la Expresión Génica , Ligamiento Genético , Humanos , Immunoblotting , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de AminoácidoRESUMEN
PURPOSE: To characterize the clinical phenotype regarding retinal function and macular appearance in patients with spinocerebellar ataxia type 7 (SCA 7), with an emphasis on electrophysiological findings. METHODS: Three patients from two Swedish families were given an ophthalmological examination including visual acuity, fundus inspection, Farnsworth's color vision test, Goldmann perimetry, full-field electroretinography (full-field ERG), multifocal electroretinography (mfERG) and optical coherence tomography (OCT). DNA was analyzed with polymerase chain reaction for CAG trinucleotide expansion repeats in the SCA 7 gene. RESULTS: Molecular analysis demonstrated abnormally expanded CAG repeats in the gene for SCA 7, which encodes the protein ataxin-7, thus confirming the diagnosis SCA 7. In the oldest patient very discreet pigmentary changes in the maculae were found, but with that exception the patients had a normal ophthalmoscopic fundus appearance and OCT demonstrated only minor changes. MfERG indicated predominantly central involvement, especially in the early disease stages, which in pace with disease progression extended from the center to the more peripheral areas. Full-field ERG in the oldest patient demonstrated bilaterally distinctly prolonged 30-Hz flicker implicit time, verifying widespread cone photoreceptor degeneration. CONCLUSIONS: The patients with genetically confirmed SCA 7 presented an early macular dysfunction, preceding any signs of abnormalities in fundus appearance. According to the electrophysiological findings the primary dysfunction involves the cone photoreceptors in the foveal region, however in an older patient involvement of cone photoreceptors throughout the retina was verified. This is in accordance with the theory that ataxin-7 interacts with CRX transcription, since it is known that mutations in the CRX gene cause cone-rod dystrophy.