Abstract
Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous malignant melanoma and the presence of autoantibodies that label neurons in the inner retina. The visual symptoms and electroretinogram (ERG) phenotype characteristic of MAR resemble the congenital visual disease caused by mutations in TRPM1, a cation channel expressed by both melanocytes and retinal bipolar cells. Four serum samples from MAR patients were identified as TRPM1 immunoreactive by 1. Labeling of ON-bipolar cells in TRPM1+/+ but not TRPM1−/− mouse retina, 2. Labeling of TRPM1-transfected CHO cells; and 3. Attenuation of the ERG b-wave following intravitreal injection of TRPM1-positive MAR IgG into wild-type mouse eyes, and the appearance of the IgG in the retinal bipolar cells at the conclusion of the experiment. Furthermore, the epitope targeted by the MAR autoantibodies was localized within the amino-terminal cytoplasmic domain of TRPM1. Incubation of live retinal neurons with TRPM1-positive MAR serum resulted in the selective accumulation of IgG in ON-bipolar cells from TRPM1+/+ mice, but not TRPM1−/− mice, suggesting that the visual deficits in MAR are caused by the uptake of TRPM1 autoantibodies into ON-bipolar cells, where they bind to an intracellular epitope of the channel and reduce the ON-bipolar cell response to light.
Highlights
Melanoma associated retinopathy (MAR) is a paraneoplastic syndrome in some patients with cutaneous malignant melanoma characterized by the presence of serum autoantibodies against retinal proteins [1,2,3,4,5,6,7,8,9] and by visual deficits including: flickering photopsias, night blindness, and a generalized constriction of visual fields
The visual symptoms and ERG phenotype characteristic of MAR are similar to those that occur in CSNB1, a congenital visual disease caused by mutations in TRPM1 and other genes required for the ON-bipolar cell light response
Sera from MAR patients have been reported to label retinal bipolar cells, and the ERG bwave in monkey has been reported to be selectively reduced by intravitreal injection of MAR IgG [11], even though for many years the MAR antigen was unknown
Summary
Melanoma associated retinopathy (MAR) is a paraneoplastic syndrome in some patients with cutaneous malignant melanoma characterized by the presence of serum autoantibodies against retinal proteins [1,2,3,4,5,6,7,8,9] and by visual deficits including: flickering photopsias, night blindness, and a generalized constriction of visual fields. Electroretinogram (ERG) recordings from MAR patients show a ‘‘negative’’ ERG in which the b-wave, originating from the depolarization of ON-bipolar cells, is more severely affected than the a-wave, originating from the lightinduced hyperpolarization of photoreceptors [1,2,9,10]. Serum from MAR patients contains autoantibodies that label retinal bipolar cells [3,4]. TRPM1 is co-localized with mGluR6 at the tips of ON-BPC dendrites where they receive input from photoreceptors and, like mGluR6, has since been found to be a major locus of mutations causing complete congenital stationary night blindness (CSNB1) in humans [15,16,17,18]. The experiences of night blindness and the ERG b-wave reduction of MAR patients is typical of CSNB1 [19]. The other known site of TRPM1 expression is melanocytes [20]
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