Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol. Vis. 11, 501-508
The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States Molecular vision
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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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Available from: Joao Borges Fortes Filho
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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).
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ABSTRACT: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP).
A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing.
Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation.
Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.
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