Human Molecular Genetics Advance Access originally published online on May 19, 2005
Human Molecular Genetics 2005 14(13):1877-1887; doi:10.1093/hmg/ddi194
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Species specific membrane anchoring of nyctalopin, a small leucine-rich repeat protein
1Academic Unit of Medical Genetics, School of Medicine and Centre for Molecular Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK, 2Bioinformatics Group, Institute of Molecular Pathology, Vienna, Austria, 3Faculty of Life Sciences, The Michael Smith Building, University of Manchester, Manchester, UK and 4Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences and Academic Unit of Eye and Vision Science, School of Medicine, University of Manchester, Manchester, UK
* To whom correspondence should be addressed at: Academic Unit of Medical Genetics, University of Manchester, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. Tel: +44 1612766276; Fax: +44 1612766606; Email: dorothy.trump{at}manchester.ac.uk
Received March 18, 2005; Accepted May 11, 2005
Mutations in the gene NYX, which encodes nyctalopin, lead to the retinal disorder congenital stationary night blindness which is characterized by defective night vision (nyctalopia) from birth. Nyctalopin is of unknown function but is predicted to be a secreted glycoprotein of the extracellular small leucine-rich repeat (SLRP) proteoglycan and protein family attached to the cell membrane in humans via a glycosylphosphatidylinositol (GPI) anchor but in mouse via a transmembrane domain. We investigated membrane association and attachment for human and mouse nyctalopin and show, conclusively, that human nyctalopin is a GPI anchored protein. In addition, the orthologous mouse protein, although it localizes to the cell surface, is not GPI anchored. We also confirm both mouse and human nyctalopins are glycosylated. Further sequence analysis suggests that chimp, dog and frog nyctalopins are likely to be GPI anchored but that rat nyctalopin is not. This is the first reported example of orthologous proteins which have different mechanisms of cell membrane attachment. Notably, the disease-causing mutations that have been identified to date in the human NYX gene are all distributed throughout the core LRR region and not in the C-terminal GPI anchor signal sequence. We propose that the presence of nyctalopin on the surface of the cell rather than the mechanism of anchoring is crucial to its function.
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