Mutations in TRPM1 Are a Common Cause of Complete Congenital Stationary Night Blindness

Bartiméus, Institute for the Visually Impaired, 3702 AD Zeist, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2009; 85(5):730-6. DOI: 10.1016/j.ajhg.2009.10.012
Source: PubMed


Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity. We report here that six out of eight female probands with autosomal-recessive complete CSNB (cCSNB) had mutations in TRPM1, a retinal transient receptor potential (TRP) cation channel gene. These data suggest that TRMP1 mutations are a major cause of autosomal-recessive CSNB in individuals of European ancestry. We localized TRPM1 in human retina to the ON bipolar cell dendrites in the outer plexifom layer. Our results suggest that in humans, TRPM1 is the channel gated by the mGluR6 (GRM6) signaling cascade, which results in the light-evoked response of ON bipolar cells. Finally, we showed that detailed electroretinography is an effective way to discriminate among patients with mutations in either TRPM1 or GRM6, another autosomal-recessive cCSNB disease gene. These results add to the growing importance of the diverse group of TRP channels in human disease and also provide new insights into retinal circuitry.

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    • "cCSNB is characterized by a drastically reduced rod b-wave response due to ON-bipolar cell dysfunction, and specific cone ERG waveforms [4]. cCSNB has been associated with mutations in NYX [5], [6], GRM6 [7], [8], TRPM1 [9]–[11] and GPR179 [12], [13], genes expressed in the inner nuclear layer (INL) of the retina [6], [14]–[17] and coding for proteins localized at the dendritic tips of ON-bipolar cells [12], [14], [15], [17]–[20]. Recently, we have identified mutations in LRIT3, a gene coding for a Leucine-Rich Repeat (LRR), immunoglobulin-like and transmembrane domains 3 protein, that lead to cCSNB [21]. "
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    ABSTRACT: Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB). The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob) phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG), respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT) reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s) associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "The data presented in this report demonstrates that TRPM1 is not essential for development of hearing or balance and it is unlikely that TRPM1 is the mechanotransduction channel in mouse auditory hair cells. This conclusion is consistent with the lack of auditory involvement in patients with cCSNB due to mutations in TRPM1 [12], [13], [14]. TRPM1 has been linked to signal transduction in DBCs, and presumably acts as the signal transduction channel [17], [31]; TRPM1 also appears to impact coat color [12] and to play a role in melanocyte physiology [32] More studies will be necessary to fully understand the role TRPM1 in the mammalian system. "
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    ABSTRACT: Sound and head movements are perceived through sensory hair cells in the inner ear. Mounting evidence indicates that this process is initiated by the opening of mechanically sensitive calcium-permeable channels, also referred to as the mechanoelectrical transducer (MET) channels, reported to be around the tips of all but the tallest stereocilia. However, the identity of MET channel remains elusive. Literature suggests that the MET channel is a non-selective cation channel with a high Ca(2+) permeability and ∼100 picosiemens conductance. These characteristics make members of the transient receptor potential (TRP) superfamily likely candidates for this role. One of these candidates is the transient receptor potential melastatin 1 protein (TRPM1), which is expressed in various cells types within the cochlea of the mouse including the hair cells. Recent studies demonstrate that mutations in the TRPM1 gene underlie the inherited retinal disease complete congenital stationary night blindness in humans and depolarizing bipolar cell dysfunction in the mouse retina, but auditory function was not assessed. Here we investigate the role of Trpm1 in hearing and as a possible hair cell MET channel using mice homozygous for the null allele of Trpm1 (Trpm1(-/-) ) or a missense mutation in the pore domain of TRPM1 (Trpm1(tvrm27/tvrm27) ). Hearing thresholds were evaluated in adult (4-5 months old) mice with auditory-evoked brain stem responses. Our data shows no statistically significant difference in hearing thresholds in Trpm1(-/-) or Trpm1(tvrm27/tvrm27) mutants compared to littermate controls. Further, none of the mutant mice showed any sign of balance disorder, such as head bobbing or circling. These data suggest that TRPM1 is not essential for development of hearing or balance and it is unlikely that TRPM1 is a component of the hair cell MET channel.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "In ordinary daylight, however, they are remarkably little handicapped, manifesting a deficit that is only revealed by specialized testing. Whether this represents plasticity—a literal rewiring of central visual circuits—or just the wealth of information present in even a partial retinal output, remains to be learned (Dryja et al., 2005; Maddox et al., 2008; Schiller et al., 1986; van Genderen et al., 2009). There is also evidence that the brain can correctly interpret new information transmitted down the same old wires. "
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    ABSTRACT: The mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The first decomposes the outputs of the rod and cone photoreceptors into ∼12 parallel information streams. The second connects these streams to specific types of retinal ganglion cells. The third combines bipolar and amacrine cell activity to create the diverse encodings of the visual world-roughly 20 of them-that the retina transmits to the brain. New transformations of the visual input continue to be found: at least half of the encodings sent to the brain (ganglion cell response selectivities) remain to be discovered. This diversity of the retina's outputs has yet to be incorporated into our understanding of higher visual function.
    Preview · Article · Oct 2012 · Neuron
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