RESUMO
PURPOSE: To report the clinical and molecular findings of a kindred with Wagner syndrome (WS) revealed by intraocular inflammatory features. METHODS: Eight available family members underwent complete ophthalmologic examination, including laser flare cell meter measurements. Collagen, type II, alpha 1, versican (VCAN), frizzled family receptor 4, low density lipoprotein receptor-related protein 5, tetraspanin 12, and Norrie disease (pseudoglioma) genes were screened with direct sequencing. RESULTS: The index case was initially referred for unexplained severe and chronic postoperative bilateral uveitis following a standard cataract surgery procedure. Clinical examination of the proband revealed an optically empty vitreous with avascular vitreous strands and veils, features highly suggestive of WS. The systematic familial ophthalmologic examination identified three additional unsuspected affected family members who also presented with the WS phenotype, including uveitis for one of them. We identified a novel c.4004-6T>A nucleotide substitution at the acceptor splice site of intron 7 of the VCAN gene that segregated with the disease phenotype. CONCLUSIONS: We present a family with WS with typical WS features and intraocular inflammatory manifestations associated with a novel splice site VCAN mutation. Beyond the structural role in the retinal-vitreous architecture, versican is also emerging as a pivotal mediator of the inflammatory response, supporting uveitis predisposition as a clinical manifestation of WS.
Assuntos
Mutação/genética , Degeneração Retiniana/complicações , Degeneração Retiniana/genética , Uveíte/complicações , Uveíte/genética , Versicanas/deficiência , Adolescente , Adulto , Idoso , Sequência de Bases , Simulação por Computador , Família , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Processamento Pós-Transcricional do RNA/genética , Sítios de Splice de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Versicanas/genética , Adulto JovemRESUMO
The frequency of disease-related large rearrangements (referred to as copy-number mutations, CNMs) varies among genes, and search for these mutations has an important place in diagnostic strategies. In recent years, CGH method using custom-designed high-density oligonucleotide-based arrays allowed the development of a powerful tool for detection of alterations at the level of exons and made it possible to provide flexibility through the possibility of modeling chips. The aim of our study was to test custom-designed oligonucleotide CGH array in a diagnostic laboratory setting that analyses several genes involved in various genetic diseases, and to compare it with conventional strategies. To this end, we designed a 12-plex CGH array (135k; 135 000 probes/subarray) (Roche Nimblegen) with exonic and intronic oligonucleotide probes covering 26 genes routinely analyzed in the laboratory. We tested control samples with known CNMs and patients for whom genetic causes underlying their disorders were unknown. The contribution of this technique is undeniable. Indeed, it appeared reproducible, reliable and sensitive enough to detect heterozygous single-exon deletions or duplications, complex rearrangements and somatic mosaicism. In addition, it improves reliability of CNM detection and allows determination of boundaries precisely enough to direct targeted sequencing of breakpoints. All of these points, associated with the possibility of a simultaneous analysis of several genes and scalability 'homemade' make it a valuable tool as a new diagnostic approach of CNMs.
Assuntos
Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Éxons , Estudos de Casos e Controles , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Feminino , Duplicação Gênica , Aconselhamento Genético , Testes Genéticos/métodos , Hemofilia A/diagnóstico , Hemofilia A/genética , Humanos , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/genética , Masculino , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant ß(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type ß(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating ß(2)-microglobulin values. The Asp76Asn ß(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of ß(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the ß(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.