Identification of Autoantibodies against TRPM1 in Patients with Paraneoplastic Retinopathy Associated with ON Bipolar Cell Dysfunction

Mineo Kondo^1#*, Rikako Sanuki^2,3#, Shinji Ueno¹, Yuji Nishizawa⁴, Naozumi Hashimoto⁵, Hiroshi Ohguro⁶, Shuichi Yamamoto⁷, Shigeki Machida⁸, Hiroko Terasaki¹, Grazyna Adamus⁹, Takahisa Furukawa^2,3*

1 Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan, 2 Department of Developmental Biology, Osaka Bioscience Institute, Suita, Osaka, Japan, 3 JST, CREST, Suita, Osaka, Japan, 4 Department of Biomedical Sciences, Chubu University, Kasugai, Aichi, Japan, 5 Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan, 6 Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan, 7 Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan, 8 Department of Ophthalmology, Iwate Medical University School of Medicine, Morioka, Iwate, Japan, 9 Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, United States of America

Abstract Top

Background

Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction.

Methodology/Principal Findings

We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera.

Conclusion/Significance

Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction.