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One of the of the rare genetic eye diseases which causes blindness is Norrie disease (ND). Effected individuals are only males since it is inherited as X-linked recessive (1,4,3). Symptoms are blindness at birth, hearing loss and mental retardation later in age (1). More severe case are, infants having developmental failure, microphthalmia and seizures (1). Mutation in Norrie Disease Pseudoglioma (NDP) gene, located on chromosome Xp11.1, is responsible for ND (1). NDP gene codes for Norrin , a cysteine rich protein having 133 amino acids with two primary domains, a signal peptide responsible for localization of the molecule and a cysteine knot that plays major role in receptor binding and signal activation (1,3). Norin binds to another protein called frizzled 4 (FZD4) which activates the wingless/integrated (Wnt) receptor signaling pathway that is important for cellular activities (1,3). There are mild and severe phenotypic effects expressed in an individual depending on the type of mutation in their NDP gene. Mutation in NDP gene is observed on three exons, that second and third exons are only translated (3). Mutations effecting the cysteine rich region of the protein, exon 2 and 3, results with severe retinal abnormalities. Mutations effecting noncysteine region of the protein expressed phenotypic effect corresponding with Familial exudative vitreoretinopathy (FEVR) disorder. Mutation in 5' UTR regulating the gene expression, and 3' UTR, responsible with mRNA localization may have major effect their function with regulating Norrin and its translation (3). Therefore overall any mutation that results dysfunctional Norrin protein can cause a major failure in normal cell development responsible for healthy eyes and other organs in body (1,3). According to the information mentioned above, Can scientist ever hope to find a cure for Norrie disease studying NDP gene mutations?
An important study was done recently to find if early vitrectomy is helpful to treat suffering infants with ND (4). Patients were selected with careful study of their medical records and family history that were diagnosed with ND (4). Children with no family history of X-linked recessive inheritance of ND and with no NDP gene mutation were classified as having bilateral persistent fetal vasculature syndrome (PFVS) disorder not ND (4). Fourteen infants had vitrectomy in one eye prior to 12 months of age. In addition to Vitectomy, the stalk tissue responsible for attachment of posterior lens to the retina was transected during the surgery (4). Observing the outcome of the surgery, 7 patients kept in one eye following up 202 months and 3 patients had no light perception bilaterally following up 61 month (4). The median age at time of the surgery for the 4 patients was 3.5 months and for the 3 patients, was 4.5 months. Conclusion of their finding was transection of stalk tissue and earliest possible surgery was beneficial to infants with ND (4). As of now vitrectomy is strongly recommended to treat blindness in infants diagnosed with ND (4).
A nonsense mutation of NDP gene was a recent discovery in a Chinese family diagnosed with ND (2). In this family, three related male individuals, expressed severe symptoms of ND, such as cerebellar atrophy, motor and mental disorders (2). The purpose of this experiment was to find evidence to relate these complex phenotypic effects to novel mutation of NDP gene (2). examination was done on a 20 year old individual as far as CT scan of his brain, ophthalmic examination, haplotype analyses and in addition , NDP DNA sequencing for 26 other individuals going back three generations of his family (2). Results for the examination were, no light perception in eye, No retinal detachment, bilateral adherent leucoma of cornea and congenital cataract (2). CT scan results, Cerebellar atrophy with widened and deepened sulci and the fifth ventricle (2). Cerebral density was normal and there was no change in the position of central structure (2). Next, DNA was extracted and stored at 20Â Â° and with PCR method, Microsatellite DNA markers were mapped to genes on the X chromosome (2). Linkage analyses and Mutation screening was also performed for all family members and for 100 healthy volunteers as normal controls, was performed in conjunction with X chromosome scans (2). From the results of Linkages analysis, Haplotype analysis and recombination mapping results, and mutation screening, they have concluded that they need additional further analyses to understand diverse and variable effects of norrin mutations (2).
Another recent study has been done regarding NDP mutation in Mexican families diagnosed with ND (3). The purpose of this experiment was to analyze new type of mutation of NDP gene n two unrelated family with ND and X-linked familial exudative vitreoretinopathy (XL-FEVR) (3). They have started the molecular examination with extracting DNA form white blood cells, PCR analysis and nucleotide sequencing of the coding region of NDP gene (3). In addition, they have done Haplotype analysis with NDP linked microsatellite markers (3). After reviewing the results, they have observed novel norrin missense mutation in two unrelated families (3). Families with x-linked were identifies with norrin mutation at arginin amino acid (3). This funding resulted in expending the NDP mutational scale (3). The phenotypic effect for this type of NDP mutation resulted with severe retinal abnormalities (3). In conclusion researchers have discovered a new type of NDP gene mutation in Mexican families (3).
In conclusion, with recent finding and research, Norrie disease treatment is very limited referring to vitrectomy which is recommended but further research and new mutation analysis depending the ethnicity of individuals , scientist are far to find new treatment for Norrie disease.