title: Autoantibodies in melanoma-associated retinopathy target TRPM1 cation channels of retinal ON bipolar cells.
abstract: Melanoma-associated retinopathy (MAR) is characterized by night blindness, photopsias, and a selective reduction of the electroretinogram b-wave. In certain cases, the serum contains autoantibodies that react with ON bipolar cells, but the target of these autoantibodies has not been identified. Here we show that the primary target of autoantibodies produced in MAR patients with reduced b-wave is the TRPM1 cation channel, the newly identified transduction channel in ON bipolar cells. Sera from two well characterized MAR patients, but not from a control subject, stained human embryonic kidney cells transfected with the TRPM1 gene, and Western blots probed with these MAR sera showed the expected band size (∼180 kDa). Staining of mouse and primate retina with MAR sera revealed immunoreactivity in all types of ON bipolar cells. Similar to staining for TRPM1, staining with the MAR sera was strong in dendritic tips and somas and was weak or absent in axon terminals. This staining colocalized with GFP in Grm6-GFP transgenic mice, where GFP is expressed in all and only ON bipolar cells, and also colocalized with Gα(o), a marker for all types of ON bipolar cells. The staining in ON bipolar cells was confirmed to be specific to TRPM1 because MAR serum did not stain these cells in a Trpm1(-/-) mouse. Evidence suggests that the recognized epitope is likely intracellular, and the sera can be internalized by retinal cells. We conclude that the vision of at least some patients with MAR is compromised due to autoantibody-mediated inactivation of the TRPM1 channel.
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. dhingra@mail.med.upenn.edu
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dhingra
authors.forename: Marie E
authors.initials: ME
authors.lastname: Fina
authors.forename: Adam
authors.initials: A
authors.lastname: Neinstein
authors.forename: David J
authors.initials: DJ
authors.lastname: Ramsey
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Alexander
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.forename: Noga
authors.initials: N
authors.lastname: Vardi
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000150:complications / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D051245:Retinal Bipolar Cells / Q000378:metabolism*; D012164:Retinal Diseases / Q000209:etiology / Q000276:immunology*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D001323:Autoantibodies; D050053:TRPM Cation Channels