Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) is a leading cause of blindness in premature children. It is a multifactorial disorder which causes fibrovascular tissue changes that affect the retina in low birth-weight and short gestational age infants. To determine the prevalence of Norrie disease (ND) gene mutations, clinical examination and molecular genetic analyses were performed in 100 pre-term babies of different ethnic backgrounds who developed advanced ROP. The leukocyte DNA was extracted, amplified by the polymerase chain reaction (PCR), and analyzed by singlestrand conformation polymorphism (SSCP), G/T and C/A scanning, and by DNA sequencing. All three exons, including splice sites and the 3Ј-untranslated region, were screened. Of the 100 patients analyzed, 2 patients with advanced ROP showed a mobility shift in the DNA. In 1 patient, this mobility shift was caused by the insertion of an additional 12-bp CT repeat in exon 1, and in the second patient, there was a 14-bp deletion in the same exon of the ND gene, as evidenced by direct sequencing of the amplified products. Similar analyses of exons 2 and 3 and the 3Ј-untranslated region failed to detect additional mutations in the gene. None of the 130 normal, unrelated controls revealed similar changes. Taking into account the above results, as well as those of other studies, it appears that the ND gene mutations can account for 3% of cases of advanced ROP. Although the ND gene is not frequently involved in advanced ROP, the present large-scale study further supports the hypothesis that genetic influences may play an important role in the development of severe ROP in some premature infants.

Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity

“…However, we did not observe any such common variant for the advanced ROP cases in our study. Likewise, the 14 bp deletion (395_409del14bp) predicted to be disease causing was observed in advanced ROP cases13; however, in the present study, the patient harbouring this change along with 3′UTR (c.*522T>C) had regressed ROP. Even in the previous studies on FEVR, similar 3′UTR variant was reported in mild cases7 thereby suggesting that 3′UTR change might be conferring protection to ROP progression.…”

Genetic Polymorphisms and Retinopathy of Prematurity

“…It has been estimated that the Norrie disease gene is responsible for approximately 3% of cases of advanced ROP, but current evidence is conflicting in different populations. [32][33][34][35] It has been suggested that in these cases ROP may have been a misdiagnosis; further work in this area is warranted. It seems unlikely, however, that it is a major factor in ROP.…”

Is ethnicity a risk factor for severe retinopathy of prematurity?

“…Animal models of ROP have shown that pigmented strains of rats are more susceptible to ischaemia-induced retinal neovascularisation than the albino counterparts 15. Recently there has been an increased interest in the role of genetic factors in ROP 16. It is possible that genetic variations among different ethnic groups could influence ROP progression.…”