TRPM1 Mutations are the Most Common Cause of Autosomal Recessive Congenital Stationary Night Blindness (CSNB) in the Palestinian and Israeli Populations

Abstract

Precise genetic and phenotypic characterization of congenital stationary night blindness (CSNB) patients is needed for future therapeutic interventions. The aim of this study was to estimate the prevalence of CSNB in our populations and to study clinical and genetic aspects of the autosomal recessive (AR) form of CSNB. This is a retrospective cohort study of Palestinian and Israeli CSNB patients harboring mutations in TRPM1 underwent comprehensive ocular examination. Genetic analysis was performed using homozygosity mapping and sequencing. 161 patients (from 76 families) were recruited for this study, leading to a prevalence of 1:6210 in the vicinity of Jerusalem, much higher than the worldwide prevalence. 61% of the families were consanguineous with AR inheritance pattern. Biallelic pathogenic TRPM1 mutations were identified in 36 families (72 patients). Two founder mutations explain the vast majority of cases: a nonsense mutation c.880A>T (p.Lys294*) identified in 22 Palestinian families and a large genomic deletion (36,445 bp) encompassing exons 2–7 of TRPM1 present in 13 Ashkenazi Jewish families. Most patients were myopic (with mean BCVA of 0.40 LogMAR) and all had absent rod responses in full field electroretinography. To the best of our knowledge, this is the largest report of a clinical and genetic analysis of patients affected with CSNB due to TRPM1 mutations.

Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients

“…Studies have found that Riggs type patients present relatively mild visual symptoms, such as restricted night blindness but normal photopic visual acuity, slight myopia, and no nystagmus [ 3 ]. The complete form of the Schubert–Bornschein type involves some notable pathogenic genes, such as X-linked recessive NYX (leucine-rich proteoglycan nyctalopin) [ 18 , 19 , 20 ], autosomal recessive GRM6 [ 21 , 22 ], TRPM1 [ 4 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], GPR179 [ 31 , 32 ], and LRIT3 [ 33 ], affecting signal transduction in the selective rod ON bipolar cell postsynaptic signal loss pathway. Typically, these complete type patients show moderate visual symptoms, including decreased visual acuity and high myopia.…”

Inducible modulation of miR-204 levels in a zebrafish melanoma model

“…In humans, melanotic melanomas are characterized by worse prognosis (Cancer Genome Atlas, 2015) and higher aggressiveness compared to amelanotic ones (Kim et al, 2017) (Damsky et al, 2011). Furthermore, they display higher resistance to radio (Brozyna et al, 2016), chemo (Xie et al, 2009) (Huang et al, 2012 (Chen et al, 2006) (Sanchez-del-Campo et al, 2009, photodynamic (Sharma and Davids, 2012) and, as we discovered, targeted therapy (Vitiello et al, 2017).…”

“…TRPM3 voltage-gated ion channel is expressed in various brain districts and in the retina (https://www.proteinatlas.org/ENSG00000083067-TRPM3/tissue). TRPM1 voltage-gated ion channel is expressed in the retina (mutations are associated with congenital stationary night blindness (AlTalbishi et al, 2019) and in melanocytes (https://www.proteinatlas.org/ENSG00000134160-TRPM1), where it is transcriptionally regulated by and acts as a downstream effector of MITF (Vitiello et al, 2017).…”

Sensing through Non-Sensing Ocular Ion Channels

“…The closing of Na + and Ca 2+ channels reduces glutamate concentration in the synapse and depolarizes the ON-bipolar cells, ERG b-wave [65][66][67][68][69]. Mutations in TRPM1 gene results in autosomal-recessive complete congenital stationary night blindness (cCSNB or CSNB1) [52,62,[70][71][72][73]. These patients, along with exhibiting nystagmus, myopia, and amblyopia, exhibit a reduced or completely absent ERG-b wave, similar to the Schubert-Bornschein patient ERG response [74], due to defective ON-bipolar cells.…”

“…PTCs account for 10–15% of all genetic diseases [ 48 , 49 ]. Several ocular channelopathies have been reported ( Table 1 ) to be associated with nonsense mutations including LCA16 [ 33 ], cone dystrophy [ 46 , 50 , 51 ], CSNB [ 52 ], bestrophinopathies [ 53 ] achromatopsia [ 54 ], and retinitis pigmentosa [ 55 ]. Table 1 represents the number of nonsense mutations reported across different disease-causing genes (HGMD database; ).…”