RESUMO
Leber congenital amaurosis (LCA) encompasses a group of severe inherited retinal dystrophies (IRDs) responsible for early childhood blindness. There are currently 25 genes implicated in the pathogenesis of these diseases, and identification of disease-causing variants will be required for personalised therapies. Whole exome and whole genome sequencing is informative for detecting novel disease-causing genes, whilst next-generation sequencing has excelled at detecting novel variants in known disease-causing genes.A global effort will be required to identify patient populations for early intervention. At the Australian Inherited Retinal Disease Registry and DNA Bank, we seek to identify genetic variants in individuals with IRDs in the Australian population to identify potential candidates for clinical trials, to inform clinical management of patients including reproductive options and to expand existing knowledge of IRDs.Due to the diversity of genes implicated, personalised strategies are likely to be the benchmark for treating these diseases, and a combined approach of different therapies may be optimal in treating some of these diseases.
Assuntos
Amaurose Congênita de Leber/genética , Medicina de Precisão , Aciltransferases/genética , Antígenos de Neoplasias/genética , Austrália/epidemiologia , Proteínas de Ciclo Celular , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Heterogeneidade Genética , Terapia Genética , Vetores Genéticos/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Amaurose Congênita de Leber/epidemiologia , Amaurose Congênita de Leber/terapia , Terapia de Alvo Molecular , Proteínas de Neoplasias/genética , Sistema de Registros , Sequenciamento do Exoma , Sequenciamento Completo do Genoma , cis-trans-Isomerases/genéticaRESUMO
PURPOSE: Abnormalities in the BEST1 gene have recently been recognised as causing autosomal recessive bestrophinopathy (ARB). ARB has been noted to have a variable phenotypic presentation, distinct from that of autosomal dominant Best vitelliform macular dystrophy (BVMD). Both conditions are associated with deposits in the retina, a reduced or absent electro-oculography (EOG) light rise, and the risk of developing angle-closure glaucoma. Herein, we describe the clinical and genetic characteristics of a young male diagnosed with ARB associated with angle-closure glaucoma resulting from a novel homozygous mutation in BEST1. METHODS: All research involved in this case adhered to the tenets of the Declaration of Helsinki. The proband underwent slitlamp examination, retinal autofluorescence imaging and optical coherence tomography after presenting with deteriorating vision. The findings prompted genetic testing with bi-directional DNA sequencing of coding and flanking intronic regions of BEST1. The proband's family members were subsequently screened. RESULTS: A provisional diagnosis of ARB was made based on the findings of subretinal and schitic lesions on fundoscopy and retinal imaging, together with abnormal EOG and electroretinography. Genetic testing identified a novel homozygous mutation in BEST1, c.636+1 G>A. Family members were found to carry one copy of the mutation and had no clinical or electrophysiological evidence of disease. The proband was additionally diagnosed with angle-closure glaucoma requiring topical therapy, peripheral iridotomies and phacoemulsification. CONCLUSIONS: Phenotypic overlap, reduced penetrance, variable expressivity and the ongoing discovery of new forms of bestrophinopathies add to the difficulty in distinguishing these retinal diseases. All patients diagnosed with ARB or BVMD should be examined for narrow angles and glaucoma, given their frequent association with these conditions.
Assuntos
Canais de Cloreto/genética , Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Glaucoma de Ângulo Fechado/genética , Mutação , Doenças Retinianas/genética , Adulto , Anti-Hipertensivos/uso terapêutico , Bestrofinas , Terapia Combinada , Eletroculografia , Eletrorretinografia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/terapia , Angiofluoresceinografia , Genes Recessivos , Glaucoma de Ângulo Fechado/diagnóstico , Glaucoma de Ângulo Fechado/terapia , Humanos , Pressão Intraocular , Iridectomia , Masculino , Facoemulsificação , Doenças Retinianas/diagnóstico , Doenças Retinianas/terapia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
Pax3 and Pax7 are powerful myogenic inducers and hence play a critical role in skeletal muscle development and regeneration. In this paper we discuss the role of Pax3 and Pax7 in dorsal patterning of the somite with subsequent determination of myogenic precursor cells for muscle formation within the developing embryo and in adult muscle. Recent evidence of the ability of stem cells to contribute to muscle regeneration in adult tissues, and the role of Pax7 in conversion of multipotent stem cells to the myogenic lineage are also discussed. Several tissue specific Pax7 transcripts that encode isoforms with different DNA binding characteristics and potentially distinct transactivation specificities are identified. The expression of a range of transcripts in the determination of different tissue lineages and distinct cell populations both in the embryo and in the adult indicates an extraordinary level of complexity. A detailed understanding of these molecules and their functions during embryogenesis and adult muscle formation is imperative for future stem cell therapies.
