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J.B. Kerrison, D. Zack, I.H. Maumenee; Candidate Gene Analysis in X–linked Congenital Nystagmus (NYS1) . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4742.
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Purpose: Congenital idiopathic or motor nystagmus (CMN) is a genetically heterogeneous disorder with identified genetic loci at Xq26–q27, Xp11.4–p11.3, and 6p12. While there is no clinically apparent defect in the afferent visual system in these patients, it is not known whether the underlying molecular defect is located in the visual sensory system or supranuclear ocular motor system. Identification of the causative gene may allow insight into the molecular determinants of ocular motor control. The purpose of this study is to identify the gene causing Xq26–q27 congenital nystagmus. Methods: Linkage Analysis, Haplotype Analysis, PCR, rtPCR, DNA sequencing. Results: Six families with CMN linked to Xq26–q27 (NYS1) have been identified. Analysis of haplotypes, places the causative gene between marker DXS8078 and DXS1211, an interval spanning 12 megabases. This region includes 55 Reference Sequence gene candidates, 37 of which are expressed in human brain or retina cDNA libraries. Sequencing of 15 candidates has identified one DNA sequence alteration, resulting in a proline to serine change and segregating with the disease in 2 families. However, this residue is not conserved between mouse and human, and the sequence alteration is present in 4.4% of normal human controls. Shared haplotypes across families due to a potential founder mutation suggest a smaller region of interest which has refined the candidate search. Conclusions: Identification of candidate genes for X–linked congenital nystagmus is hampered by the large genetic interval and the lack of knowledge as to where the primary biologic defect is located. Strategies being employed to refine the candidate search include microarray analysis and rtPCR using RNA derived from lymphoblast lines.
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