RESUMEN
PURPOSE: Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. METHODS: The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. RESULTS: Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. CONCLUSIONS: An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.
Asunto(s)
Ceguera/congénito , Oftalmopatías/genética , Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Variación Genética , Proteínas del Tejido Nervioso/genética , Displasia Retiniana/genética , Cuerpo Vítreo , Adolescente , Preescolar , Codón sin Sentido , Análisis Mutacional de ADN , Sordera/genética , Exudados y Transudados , Femenino , Genotipo , Humanos , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , EspañaRESUMEN
Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A.
Asunto(s)
Proteínas de Filamentos Intermediarios/genética , Glicoproteínas de Membrana , Mutación , Proteínas del Tejido Nervioso/genética , Retinitis Pigmentosa/genética , Adulto , Aberraciones Cromosómicas , Electrorretinografía , Femenino , Genes Dominantes , Humanos , Masculino , Persona de Mediana Edad , Periferinas , Fenotipo , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Retinitis Pigmentosa/diagnóstico , Agudeza VisualRESUMEN
PURPOSE: X-linked juvenile retinoschisis (XLRS) is one of the most common causes of juvenile macular degeneration in males, characterized by microcystic changes, splitting within the inner retinal layer (schisis), and the presence of vitreous veils. This study was conducted to describe and further correlate specific genetic variation in Spanish patients with XLRS with clinical characteristics and additional ophthalmic complications. METHODS: The study was performed in 34 Spanish families with XLRS, comprising 51 affected males. Thorough clinical ophthalmic and electrophysiological examinations were performed. The coding regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced. Haplotype analyses were also performed. RESULTS: Twenty different mutations were identified. Ten of the 20 were novel and 3 were de novo mutational events. The most common mutation (p.Gln154Arg; 6/20) presented a common haplotype. RS1 variants did not correlate with ophthalmic findings and were not associated with additional ophthalmic complications. CONCLUSIONS: The prevalent p.Gln154Arg mutation is first reported in this work and presents a common origin in Spanish patients with XLRS. In addition, de novo mutations mainly occur in CG dinucleotides. Despite the large mutational spectrum and variable phenotypes, no genotype-phenotype correlations were found. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide a prognosis.