TRPM1 – Congenital Stationary Night Blindness

Transient receptor potential cation channel subfamily M member 1 (TRPM1) is a non-selective cation channel critical for ON bipolar cell depolarization in the retina. Biallelic loss-of-function variants in TRPM1 underlie autosomal recessive congenital stationary night blindness (Congenital stationary night blindness), characterized by absent scotopic b-wave on electroretinogram and lifelong nyctalopia.

Genetic evidence includes five different TRPM1 mutations in three unrelated Japanese patients with complete CSNB (PMID:20300565), biallelic variants in 72 patients across 36 consanguineous families from Palestinian and Israeli cohorts (PMID:31427709), six of eight Indian families with complete CSNB (PMID:24715752), and additional series in Korean and Taiwanese patients confirming autosomal recessive inheritance.

Over 60 distinct pathogenic variants have been reported, predominantly frameshift (e.g., c.910_911del (p.Ser304ArgfsTer15)), nonsense, and canonical splice-site changes. Two founder alleles—a c.88>T (p.Lys294Ter) in Palestinian families and a multiexon deletion of exons 2–7 in Ashkenazi Jews—account for >80% of regional cases (PMID:31427709; PMID:31645983). Rare missense variants have also been described with deleterious functional impact.

Functional assays demonstrate that splice-site and missense variants disrupt TRPM1 protein production or mislocalize channels in bipolar cells, leading to a "negative" ERG b-wave (PMID:20300565). Trpm1(−/−) and knock-in mouse models recapitulate absent b-waves with normal a-waves, mirroring the human phenotype. A dominant-negative p.Ala1068Thr knock-in further confirms dose-dependent channel function (PMID:22896717).

One report of unilateral cataract in a TRPM1 compound heterozygote noted CSNB features but could not link TRPM1 to lens opacity (PMID:35872165). No studies have refuted the TRPM1–CSNB association.

In summary, the cumulative genetic, segregation and experimental data meet criteria for a definitive autosomal recessive TRPM1–CSNB association. TRPM1 variant analysis is recommended for patients with congenital night blindness, nyctalopia, nystagmus, and high myopia to inform diagnosis and guide future gene-targeted therapies.

References

• Molecular Vision • 2010 • TRPM1 mutations are associated with the complete form of congenital stationary night blindness. PMID:20300565
• Scientific Reports • 2019 • TRPM1 Mutations are the Most Common Cause of Autosomal Recessive Congenital Stationary Night Blindness (CSNB) in the Palestinian and Israeli Populations. PMID:31427709
• Human Genome Variation • 2019 • A founder deletion in the TRPM1 gene associated with congenital stationary night blindness and myopia is highly prevalent in Ashkenazi Jews. PMID:31645983
• Molecular Vision • 2014 • Molecular profiling of complete congenital stationary night blindness: a pilot study on an Indian cohort. PMID:24715752
• Journal of Neurophysiology • 2012 • Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. PMID:22896717
• Journal of AAPOS • 2022 • Unilateral cataract and congenital stationary night blindness in a child with novel variants in TRPM1. PMID:35872165

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