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HB Stoehr, C Berger, S Froehlich, BH F Weber; Identification of a Novel Retina and Brain Specific Gene, NETO1, and Its Assessment in Age-related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2415.
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Purpose: Age-related macular degeneration (AMD) is an increasingly common, multifactorial disorder causing severe vision impairment among the elderly population. To elucidate the molecular basis of AMD, we are aiming to identify predisposing genetic factors and to determine their contribution towards the disease process. Methods: To generate a comprehensive and complete catalog of genes preferentially active in the human retina we performed a systematic expression analysis of genes represented by UniGene ESTclusters highly enriched of ESTs from retinal cDNA libraries. A combination of molecular genetics methods and biocomputation was used to isolate and characterize the gene originally identified as the retina-specific EST cluster Hs.60563. Its possible role in AMD was studied by mutation analysis in a large cohort of AMD patients using denaturing gradient gel electrophoresis and denaturing high-performance liquid chromatography. Results: A novel retina and brain specific gene from mouse and human was cloned, NETO1 (neuropilin and tolloid like-1), encoding a putative transmembrane protein with an N-terminal signal sequence and two conserved extracellular CUB domains followed by a single copy of the low density lipoprotein class A (LDLa) module. The human NETO1 gene comprises 13 exons on chromosome 18q22-q23 and gives rise to three different mRNA isoforms. Utilization of two alternative leader exons leads to transcripts that translate into putative signal peptides with distinct sequence composition but otherwise do not affect the primary structure of the mature NETO1 protein. Usage of exon 5 is restricted to the retinal tissue and generates a truncated transcript that codes for a putative soluble protein, termed sNETO1, with only one copy of the CUB domain while lacking the LDLa module. Mutation screening of affected AMD individuals is currently in progress. Conclusion: NETO1 represents a novel member of CUB and LDLa containing proteins. The specific expression of NETO1 in retina and brain and the discovery of a retina-specific splice variant suggests an important function of NETO1 in these tissues. This makes NETO1 an interesting candidate gene to be tested for a possible involvement in retinal disease.
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