Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity.
ABSTRACT Retinopathy of prematurity (ROP) is a leading cause of visual loss in the pediatric population. Mutations in the Norrie disease gene (NDP) are associated with heritable retinal vascular disorders, and have been found in a small subset of patients with severe retinopathy of prematurity. Varying rates of progression to threshold disease in different races may have a genetic basis, as recent studies suggest that the incidence of NDP mutations may vary in different groups. African Americans, for example, are less likely to develop severe degrees of ROP. We screened a large cohort of ethnically diverse patients for mutations in the entire NDP.
A total of 143 subjects of different ethnic backgrounds were enrolled in the study. Fifty-four patients had severe ROP (Stage 3 or worse). Of these, 38 were threshold in at least one eye (with a mean gestational age of 26.1 weeks and mean birth weight of 788.4 g). There were 36 patients with mild or no ROP, 31 parents with no history of retinal disease or prematurity, and 22 wild type (normal) controls. There were 70 African American subjects, 55 Caucasians, and 18 of other races. Severe ROP was noted in 29 African American subjects, 17 Caucasians, and 8 of other races. Seven polymerase chain reaction primer pairs spanning the NDP were optimized for denaturing high performance liquid chromatography and direct sequencing. Three primer pairs covered the coding region, and the remaining four spanned the 3' and 5' untranslated regions (UTR).
Six of 54 (11%) infants with severe ROP had polymorphisms in the NDP. Five of the infants were African American, and one was Caucasian. Two parents were heterozygous for the same polymorphism as their child. One parent-child pair had a single base pair (bp) insertion in the 3' UTR region. Another parent-child pair had two mutations: a 14 bp deletion in the 5' UTR region of exon 1 and a single nucleotide polymorphism in the 5' UTR region of exon 2. No coding region sequence changes were found. No polymorphisms were observed in infants with mild or no ROP, or in the wild type controls.
Of the six sequence alterations found, five were novel nucleotide changes: One in the 5' UTR region of exon 2, and four in the 3' UTR region of exon 3. The extent of NDP polymorphisms in this large, racially diverse group of infants is moderate. NDP polymorphisms may play a role in the pathogenesis of ROP, but do not appear to be a major causative factor.
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ABSTRACT: RESUMO Este artigo aborda aspectos atuais da Retinopatia da Prematuridade, entidade clínica responsável pela maior quantidade de crianças cegas em todo o mundo nos dias de hoje. Procura chamar a atenção para a importância da triagem na busca da doença em todos os prematuros de muito baixo peso e a necessidade de que a retinopatia seja identificada no momento adequado, quando ainda existe chance para o tratamento que deverá ser feito, preferencialmente, durante o tempo de permanência da criança no Centro de Neonatologia. O exame oftalmológico inicial deve ser realizado sob oftalmoscopia binocular indireta e dilatação das pupilas, entre a 4ª e a 6ª semana de vida, em todos os recém-nascidos com peso igual ou menor do que 1500 gramas e/ou com idade gestacional igual ou inferior a 32 semanas. O acompanhamento das crianças com ou sem retinopatia identificada deverá seguir periodicamente até a normalização da vascularização da retina temporal na Zona III, o que poderá tardar até mais do que os primeiros seis meses de vida e deverá ser mantido pelos dois primeiros anos para a prevenção da ambliopia e do estrabismo e para a correção das altas ametropias relaci-onadas com a prematuridade. Durante o texto ficam convencionadas as seguintes defi-nições: · Prematuridade: nascidos com menos de 37 semanas de idade gestacional; · Prematuridade extrema: nascidos com menos de 28 semanas de idade gestacional; · Baixo peso: nascidos com menos de 2000 gramas; · Muito baixo peso: nascidos com menos de 1500 gramas; · Extremo baixo peso: nascidos com menos de 1000 gramas. Descritores: Retinopatia da prematuridade/terapia; Cegueira/prevenção & controle; Prevalência; Revisão Rev Bras Oftalmol. 2006; 65 (4): 246-58 247 INTRODUÇÃO A pesar de ter sido descrita há mais de 50 anos, a Retinopatia da Prematuridade (ROP) se tornou uma das maiores causas de cegueira infantil (definida pela OMS como cegueira ocorrendo até os 15 anos de idade) nos países desenvolvidos, em função da maior sobrevivência de recém-nascidos pre-maturos (RNP) com menor peso de nascimento e com menor idade gestacional (IG).Revista brasileira de oftalmologia 01/2006; 65(4):246-258. · 0.16 Impact Factor
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ABSTRACT: Retinopathy of prematurity (ROP) is a complex disease with a genetic predisposition, but little is known about its genetic background. It has a clinical resemblance to familial exudative vitreoretinopathy (FEVR), a hereditary disease characterized by defects in the development of retinal vessels. Several studies have suggested that mutations in the causative genes for FEVR may account for a proportion of advanced ROP, but conflicting data have also been reported for some variants. To address the possibility of genetic involvement of FEVR genes in ROP, we performed comprehensive sequence analyses of 53 Japanese patients with advanced ROP for the FEVR-causing genes. Peripheral blood DNA was obtained from 53 patients referred to our hospitals for retinal surgery. Polymerase chain reaction followed by direct sequencing of the coding regions of the known FEVR-causing genes (FZD4, LRP5, TSPAN12, and NDP) and a noncoding exon of the NDP gene was performed. Possible pathogenicity of the sequence changes were analyzed by orthologous protein sequence alignment and by computational predictions. We identified six different nonsynonymous DNA variants in the coding region of either the FZD4 gene (p.H69Y, p.R127H, and p.Y211H) or the LRP5 gene (p.R1219H, p.H1383P, and p.T1540M) in seven patients. The corresponding codons of these changes were highly conserved among species, and these changes were predicted to be pathogenic by at least two of four computational prediction programs. No such changes were found in the TSPAN12 and NDP genes. Six possibly pathogenic variants of FZD4 or LRP5 were found in seven advanced ROP patients. Although these variants do not yet provide definitive evidence that they are causal, the results imply a role of the FZD4 and LRP5 genes in the development of advanced ROP.Molecular vision 02/2013; 19:476-85. · 2.25 Impact Factor
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ABSTRACT: During retinal neurogenesis, diverse cellular subtypes originate from multipotent neural progenitors in a spatiotemporal order leading to a highly specialized laminar structure combined with a distinct mosaic architecture. This is driven by the combinatorial action of transcription factors and signalling molecules which specify cell fate and differentiation. The emerging approach of gene network analysis has allowed a better understanding of the functional relationships between genes expressed in the developing retina. For instance, these gene networks have identified transcriptional hubs that have revealed potential targets and pathways for the development of therapeutic options for retinal diseases. Much of the current knowledge has been informed by targeted gene deletion experiments and gain-of-functional analysis. In this review we will provide an update on retinal development gene networks and address the wider implications for future disease therapeutics.Progress in Retinal and Eye Research 11/2012; 33. DOI:10.1016/j.preteyeres.2012.10.003 · 9.90 Impact Factor