RESUMO
Mutations in the gene encoding the transcription factor neural retina leucine zipper (NRL) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone-rod homeobox (CRX), to transactivate a human rhodopsin (RHO) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family. The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL-linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas do Olho/genética , Mutação de Sentido Incorreto , RNA Interferente Pequeno/genética , Retinose Pigmentar/genética , Adulto , Idoso , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Genes Dominantes , Heterogeneidade Genética , Variação Genética , Proteínas de Homeodomínio/genética , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Rodopsina/genética , Transativadores/genética , Ativação Transcricional , Regulação para CimaRESUMO
OBJECTIVE: Genetic characterization of a series of patients with autosomal dominant retinitis pigmentosa (ADRP). METHODS: All patients underwent complete ophthalmological examination including computerized perimetry, electroretinography and occasionally fluorescein angiography. Blood samples were drawn for genetic analysis of candidate genes namely rhodopsin (RHO), peripherin-RDS, ROM-1, CRX, RP1 and NRL. RESULTS: 148 ADRP index cases were examined at our hospital from June 1991 to September 2001. Genetic analysis detected the following mutations: 29 different families (19.5%) carried a RHO mutation among which the Pro-347-Leu was the most frequent one, five different RP-1 mutations (3.3%), 2 RDS mutations and one NRL mutation, which is the second reported in the world literature. CONCLUSIONS: RHO followed by RP1 are the most frequent ADRP-causing genes in our series as in other published ones, and RDS causes mainly macular dystrophies. Molecular characterization was possible in 37 families (25%) which is of great interest for visual prognosis and genetic counselling.
Assuntos
Proteínas do Olho/genética , Glicoproteínas de Membrana , Mutação , Retinose Pigmentar/genética , Substituição de Aminoácidos , Fatores de Transcrição de Zíper de Leucina Básica , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Genes Dominantes , Proteínas de Homeodomínio/genética , Humanos , Proteínas de Filamentos Intermediários/genética , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Periferinas , Mutação Puntual , Retinose Pigmentar/sangue , Retinose Pigmentar/patologia , Rodopsina/genética , Tetraspaninas , Transativadores/genéticaRESUMO
Retinitis pigmentosa (RP) is the most frequent form of inherited retinopathy. RP is genetically heterogeneous with autosomal dominant, autosomal recessive and X-linked forms. Autosomal dominant retinitis pigmentosa (adRP) accounts for about 20-25% of all RP cases. At least ten adRP loci have so far been mapped. However, mutations causing adRP have been identified only in four retina-specific genes: RHO (encoding rhodopsin) in approximately 20% of adRP families, peripherin/RDS (3-5% of adRP) and recently RP1 (Pierce et al., 1999, Sulivan et al., 1999) and NRL gene. Only one mutation in the NRL gene causing adRP has so far been reported (Bessant et al., 1999). Here we report a novel mutation Pro51Leu in an adRP Spanish family supporting that mutation in NRL is the cause of adRP. A second missense mutation Gly122Glu has been observed in a simplex RP patient that may represent a sporadic case of retinitis pigmentosa. Hum Mutat 17:520, 2001.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas do Olho/genética , Retinose Pigmentar/genética , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Genes Dominantes , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Polimorfismo Conformacional de Fita SimplesRESUMO
Mutations in the rhodopsin cause of retinitis pigmentosa autosomal dominant (ADRP). We report a large family affected with ADRP. Analysis by denaturant gradient gel electrophoresis and direct DNA sequence detected an heterozygous G to T transversion in the exon 3 of the rhodopsin gene. This mutation damages a restriction site for Taq I enzyme and produces the change Asp-190-Tyr in rhodopsin. All carriers of the mutation show a regional RP phenotype. This mutation is responsible for the disease in this family.
Assuntos
Aberrações Cromossômicas/genética , Expressão Gênica/genética , Mutação Puntual/genética , Retinose Pigmentar/genética , Rodopsina/genética , Cromossomo X/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pré-Escolar , Transtornos Cromossômicos , Citogenética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Ophthalmic evolution was studied for 2 years in 17 patients with insulin-dependent diabetes mellitus and background diabetic retinopathy. Nine patients were treated with triflusal, a new platelet antiaggregant drug, and the eight remaining patients, with similar clinical and biological characteristics, were considered the control group. At the end of the study the ophthalmic evolution was different in the two groups. In the control group the degree of fluorescein leakage and the number of microaneurysms increased, while in the triflusal-treated group both parameters were reduced. There were no differences in visual acuity and computerised perimetry between the groups. Our results suggest that platelet antiaggregant therapy can be useful in the treatment of background diabetic retinopathy.