Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness

Abstract

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440(∗)]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384(∗)]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs(∗)59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated.

Congenital stationary night blindness with hypoplastic discs, negative electroretinogram and thinning of the inner nuclear layer

“…Likewise, mutations in NYX, GPR179, and LRIT3, may cause complete CSNB [1]. These proteins, including TRPM1, are all localized to the dendritic tips of ON-bipolar cells, and are all implicated in autosomal recessive complete CSNB with negative electroretinogram [9][10][11][12][13].…”

“…TRPM1 is believed to be the cation channel in the ON bipolar cells that is responsible for the depolarization of these cells during light stimulation as follows. In the dark, glutamate is released from photoreceptors, binds to the metabotropic gluatamate receptor mGluR6 (encoded by GRM6) on the rod bipolar cells [9], which in turn leads, by an unidentified mechanism which probably involves nyctalopin (NYX) [10], G-Protein coupled Receptor 179 (GPR179) [11], and Leucine-rich Repeat, Immunoglobulin-like, and Transmembrane 7 domains-containing protein 3 (LRIT3) [12], to the closure of the cation channel TRPM1 [1]. Upon light exposure, the cessation of glutamate release from the photoreceptors leads to the opening of TRPM1, in turn leading to ON bipolar cell depolarization, giving rise to the b-wave.…”

Oligomeric State of Purified Transient Receptor Potential Melastatin-1 (TRPM1), a Protein Essential for Dim Light Vision

“…In addition, several transient receptor potential proteins have been shown to form functional heteromers with other members of the same family including proteins of the TRPM (53, 54), TRPC (55)(56)(57), and TRPV (58, 59) families. Several other integral membrane proteins are required for the depolarizing light response of ON bipolar cells, namely mGluR6 (4), GPR179 (60 -62), and LRIT3 (63,64). Nyctalopin, which is an integral membrane protein in mice but not humans (65,66), is also required (67)(68)(69)(70).…”

Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

“…Previous publications report TRPV1 protein expression in the inner retina of rodents (Sappington et al, 2009& Leonelli et al, 2009& 2013, goldfish (Zimov &Yazulla, 2007), and non-human primates (Sappington et al, 2015). Similar to the role of TRPV1 in the PNS, the protein is thought to regulate Ca 2+ in the ganglion cell layer (GCL) and inner nuclear layer (INL) of the retina (Sappington et al, 2009(Sappington et al, & 2015Leonelli et al, 2010;Ryskamp et al, 2014).…”