Study Proposal: Causative Mutations in Optic Neuropathy

Study Proposal Causative Mutations in Optic NeuropathyOptic neuropathy refers to de factorration of optic middle. It is often described as middle cachexy that bureau loss of few or most of optic face vulcanized fibers 1. It house be symmetric or bilateral based on unhealthful or nutritional ( vitamin B12 or folate deficiency) insults and ge give the sackic defects 4. In genetically inherited optic atrophies, retinal ganglion cells and optic brass section fiber mold ar damaged. This damage can be focal (affects macular beam of optic memorial tablet) or generalized 6. The axons of retinal ganglion cells arise from retina and from optic nerve. The optic nerve enter cortex via optic magnetic disk where input signal is bear upon into vision. The retinal ganglion cells or nerve cells of inner retina form 1.2 million nerve fibers 1. The key features of optic neuropathy results from death of these nerve cells or neurons.Autosomal recessive optic atrophies (ROAs) indicate los s of nerve fibers that form optic disc, optic nerve, optic chiasm and optic tracts net bookmark. The only key feature of marooned ROAs is optic nerve degeneration. To date defects in genes coding for mitochondrial proteins leads to isolated ROAs 4.The genetically inherited atrophies can be familial that follows Mendelian pattern of heritage (X-linked recessive, autosomal recessive and autosomal dominant) or non Mendelian (mitochondrial) 2. In autosomal recessive Mendelian pattern of inheritance, two copies of mutant allele in affected person and one copy of mutant allele in carrier are surrender. When two carriers mate, there is an equal chance (25%) of creation affected and unaffected. There is a 50% chance of being heterozygous (unaffected carrier). But in autosomal dominant pattern of inheritance, affected souls cave in one mutant copy of allele so e precise individual has 50% chance of being affected or being normal.In the pure congenital autosomal recessive optic atrophy, symptoms like opthalmic impairment appear very too soon and are present at birth or appear in firstly year of life. abnormal individuals are severely impaired visually leading to visual constipation or complete blindness. It is never associated with neurological disorders. It can be diagnosed very early, usually before the age of 4 years. Fundus examination reveals optic disc pallor temporally or bilaterally. A cupping may bugger off with age 3. Affected individuals suffer from central scotoma, photophobia and also get down red green color confusion 6. Family history is critical for diagnosing Hereditaryopticneuropathies from clinical signs to diagnosis.Clinical diagnosis involves fundoscopy, visual field testing, fluorescent dye angiography, optical coherence tomography scan of the retinal nerve fiber layers, color vision analysis and standard electroretinogram. Damage from optic nerve atrophy cannot be reversed 4.To clinically distinguishes it from LHON flourscene angiogra phy was done which fails to show each peripapillary microvascular changes, beside this retinal activity is also normal corroborate by electroretinogram. Pathology of arOA is confirmed by testing visual evoked potential which was gibely absent in affected individuals. Central or cecocentral faults are diagnosed with visual field testing. Lesion in the fovea or papillomacular bundle leads to cental scotoma which in the end affects the central fixation. Thinning of retinal nerve fiber layer is diagnosed through optical coherence tomography scan 3, 4, clinical diagnosis. Papillomacular bundle leads to the denotation of cecocentral sctoma towards blind spot.There is no effective treatment for optic atrophy because degeneration of nerve fibers is irreversible process. Although further damage can be prevented by early diagnosis and by treating underlying causes of the disorder net bookmark. As environmental factor play their exercise in every aspect of life likewise in this disord er alcohol role and smoking should be strictly prohibited Hereditaryopticneuropathies from clinical signs to diagnosis. Genetic counselling and seemly certifiedness of people is very important to prevent such(prenominal)(prenominal) genetic disorders without any effective treatment.New therapies are being develop by designing animal models or by clinical mental testing on affected humans these therapies mainly focuses in preventing oxidative stress. living creature models have been designed for testing the various treatments in case of Leber transmitted optic neuropathy Treatment of hereditaryopticneuropathies.arOA is divided into syndromic and non-syndromic form, syndromic arOA involve multiple organs other than midriff which are effected just like wolfram syndrome 6, net bookmarks. dapple in non-syndromic optic nerve is affected only and it also shows familial transmission more than one members of alike(p) family can also be affected Hereditaryopticneuropathies from cli nical signs to diagnosis.OPA 6 and 7 are the two loci which are characterized till now, novelty in any one of two leads to arOA. disease causing gene has been localized at chromo near 8q21q22 (Zmax of 3.41 at h0 for D8S270). D8S1794 and D8S1702 markers present on OPA6 in a 12Mb interval 6. OPA7 containing 40 know genes, only one gene TMEM126A screened as a causative agent of non-syndromic arOA 4, 7. TMEM126A is homozygous nonsense mutation characterized as first known mutation in case of isolated arOA, this gene transcribed into mitochondrial transmembrane protein.TMEM126A helps in early nucleation of mitochondrial complexes that is why it is also termed as mitochondria-localized mRNA (MLR) protein. It play important role in function of retinal ganglion cells by arranging protein complexes essential for the proper functioning of RGCs. It is hypothesized that TMEM126A may accelerate the rate at which protein complex assemble, which other occurs slowly that ultimately affect high e nergy demanding RGCs. While in other tissues the effect of this mutation may be substituted by several(prenominal) other protein of TMEM family 4, 7.TMEM126A transcribe single ubiquitous transcript of 770bp that contain total five exons four coding and one non-coding exon. TMEM126A present on chromosome 11 and its span is 8.5 kb. Testis, foetal retinal pigmentary epithelium (RPE), fetal retina, brain (whole), cerebellum, fetal brain and skeletal muscle are the sites where strong expression of TMEM126A has been observed. solid amount of specific mRNA in the ganglion cell layer, optic nerve head, the outer ellipsoide length of photoreceptor inner segments, and the outer plexiform layer is detected by the process of insitu hybridization in mouse i.e. 8 month old. In the photoreceptor outer segments and outer nuclear layer (ONL) no labeling is noticed. Mitochondria specific of import subunit of the ATP synthase is Immunolocalized on retinal sections of the same mouse which resulted into the same pattern of expression. So it is confirmed that TMEM126A transcribe mitochondrial localized m RNA. gene linkage analysis is the process helps in finding mutation or gene resulted into arOA. Potential functionality of genes with their chromosomal location is associated through this statistical method. During chromosomal recombination markers present fuddledly or on the same area on chromosome entrust remain attached together are transmitted as such in offsprings this idea is exploited in linkage analysis. If in an individual disease gene is transmitted along with some specific markers it means disease causing gene is present close to these markers. Those disorders that follow Mendelian inheritance pattern can easily be analyzed through this process 5.This study will be the first step which further helps in identifying the causative gene responsible for arOA in Pakistani population and also help in designing cure tools for the benefit of affected persons. By conducting these type of studies we can also aware our population about such type of rare disorders.