TRPM3 encodes a protein, transient receptor potential cation channel subfamily M member 3, which is temperature- and neurosteroid-sensitive. The first study by Bennett et al in 2014 (PMID: 25090642). reported TRPM3 in relationship to autosomal dominant cataract with or without high pressure glaucoma in a 5-generation Caucasian-American pedigree. Genome-wide linkage analysis mapped the cataract locus to the pericentric region of human chromosome 9, and exome sequencing of the linked region identified a heterozygous substitution of isoleucine-to-methionine at codon 65 (c.195A>G, p.Ile65Met) in TRPM3 transcript NM_001007471.2. This variant segregated fully with the cataract in the family. Functional studies of the human p.Ile65M knock-in mice model showed that heterozygous Trpm3-mutant mice developed cataract (2021, PMID: 33484482) and lens from the Trpm3-mutation mice displayed elevated cytosolic Ca2+ levels and an imbalance of sodium (Na+) and potassium (K+) ions, coupled with increased water content, suggesting failure of Trpm3-mutant lens to osmoregulation and gain-of-function as the disease mechanism (2024, PMID: 38334649). The second study by Li et al in 2018 (PMID: 29914532) sequenced 80 cataract-associated genes for a cohort of 39 Chinese pediatric cataract cases and detected a heterozygous variant, c.3920G>C, p.Arg1307Thr in TRPM3 transcript NM_206944.4, in one family. This variant segregated with the cataract in the family. No data of functional study is available for this variant. As of this curation, only two above-mentioned variants in TRPM3 have been linked to inherited form of cataract in two families. As of the genetic evidence, the case level and segregation data were scored up to 3.6 points. The functional experimental data from the human p.Ile65Met knock-in mouse model was scored up to 3.25 points. Taking together 6.85 points is scored in total with moderate evidence to support the TRPM3-cataract relationship. While more evidence is needed to establish this relationship definitively, no contradictory evidence has merged. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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