Riggs-type dominant congenital stationary night blindness: ERG findings, a new GNAT1 mutation and a systemic association.

PURPOSE: Complete congenital stationary night blindness (CSNB) is most often x-linked or recessive, and associated with a transmission defect from photoreceptors to bipolar cells. This produces a characteristic "negative" Schubert-Bornschein type of scotopic rod-cone electroretinogram (ERG) with a large a-wave and minimal b-wave. CSNB from abnormalities in phototransduction can be recessive or dominant and is much less common. This produces a Riggs type of ERG with loss of the rod a-wave as well as the b-wave. We report the clinical and ERG findings from a family with autosomal dominant CSNB that was shown previously to have a new GNAT1 mutation with a novel mechanism of action. They provide a classic demonstration of the Riggs-type ERG and have an unusual systemic association. METHODS: Clinical case report of a father and daughter. RESULTS: A Chinese father and daughter presented with good visual acuity, moderate myopia, and lifelong night blindness. Both show normal fundi except for mild myopia, and fundus autofluorescence and OCT images are normal. Their ERGs illustrate the typical Riggs-type ERG with no rod a-wave (they have only a small cone-dominated combined response). They also have postural orthostatic tachycardia syndrome (POST), which is an autonomic dysfunction disorder thought usually to be sporadic. The retinal gene analyses revealed no abnormalities that might account for POST. CONCLUSIONS: Our family's ERG showed essentially no rod response, consistent with a Danish GNAT1 pedigree but different from the Nougaret GNAT1 pedigree that shows partial preservation of rod signal. A genetic connection between CSNB and POST would be intriguing, but we found no evidence for this.

LRIT3 is essential to localize TRPM1 to the dendritic tips of depolarizing bipolar cells and may play a role in cone synapse formation.

Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). The exact role of LRIT3 in ON-bipolar cell signaling cascade remains to be elucidated. Recently, we have characterized a novel mouse model lacking Lrit3 [no b-wave 6, (Lrit3(nob6/nob6) )], which displays similar abnormalities to patients with cCSNB with LRIT3 mutations. Here we compare the localization of components of the ON-bipolar cell signaling cascade in wild-type and Lrit3(nob6/nob6) retinal sections by immunofluorescence confocal microscopy. An anti-LRIT3 antibody was generated. Immunofluorescent staining of LRIT3 in wild-type mice revealed a specific punctate labeling in the outer plexiform layer (OPL), which was absent in Lrit3(nob6/nob6) mice. LRIT3 did not co-localize with ribeye or calbindin but co-localized with mGluR6. TRPM1 staining was severely decreased at the dendritic tips of all depolarizing bipolar cells in Lrit3(nob6/nob6) mice. mGluR6, GPR179, RGS7, RGS11 and Gß5 immunofluorescence was absent at the dendritic tips of cone ON-bipolar cells in Lrit3(nob6/nob6) mice, while it was present at the dendritic tips of rod bipolar cells. Furthermore, peanut agglutinin (PNA) labeling was severely reduced in the OPL in Lrit3(nob6/nob6) mice. This study confirmed the localization of LRIT3 at the dendritic tips of depolarizing bipolar cells in mouse retina and demonstrated the dependence of TRPM1 localization on the presence of LRIT3. As tested components of the ON-bipolar cell signaling cascade and PNA revealed disrupted localization, an additional function of LRIT3 in cone synapse formation is suggested. These results point to a possibly different regulation of the mGluR6 signaling cascade between rod and cone ON-bipolar cells.