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

Abstract

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.

Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome

“…31 Our patient has a markedly abnormal ERG with a depressed b-wave, a finding consistent with loss of TRPM1 and CSNB. [18][19][20][21] It is possible that the differential expression of LUM in the proband may be secondary to an indirect effect of CSNB.…”

“…Although the CHRNA7 deletion is posited to cause seizures and neuropsychiatric disturbances, homozygous TRPM1 (transient receptor potential cation channel, subfamily M, member 1) deletion appears to cause visual impairment, in particular congenital stationary night blindness (CSNB). [17][18][19][20][21] Although analysis of structural variants are beginning to provide insight into functional genomics, 22 the exact relationships between altered CHRNA7 and TRPM1 gene expression, the associated abnormal phenotypes, and the roles of the other genes within the deleted region remain unclear. It is entirely possible that the pathogenic mechanisms underlying CHRNA7 and TRPM1 loss are a direct consequence of the deletion.…”

Teleost polarization vision: how it might work and what it might be good for

“…These cells express the metabotropic glutamate receptor, mGluR6 [47 -51]. Activation of mGluR6 by glutamate leads, via an intracellular cascade, to the closure of TrpM1 channels on the dendrites of ON-BCs [52][53][54]. Glutamate induces a hyperpolarization of these neurons.…”

G-protein–mediated inhibition of the Trp channel TRPM1 requires the Gβγ dimer

“…Soon after, it was shown that ON bipolar cell function was absent or severely impaired in a mouse model that lacked TRPM1 expression (2-4), although there is evidence that one or more classes of cone-driven ON bipolar cells may use an additional channel (3). Mutations in TRPM1 have now been positively linked to CSNB in humans as well (5)(6)(7). Taken together, studies of mouse, horse, and human provide convincing evidence that the ON bipolar cell transduction channel is composed of TRPM1, either alone or in conjunction with other channels.…”