A number sign (#) is used with this entry because of evidence that cataract-50 with or without glaucoma (CTRCT50) is caused by heterozygous mutation in the TRPM3 gene (608961) on chromosome 9q21. One such family has been reported.

CTRCT50 is characterized by pediatric or early-onset cataract, with more than half of affected individuals exhibiting high-tension glaucoma. Variable anterior segment defects have also been reported (Bennett et al., 2014).

Bennett et al. (2014) reported a large 5-generation Caucasian American family segregating autosomal dominant cataract with or without glaucoma and with mutation in the TRPM3 gene. The family was ascertained through medical records, and retrospective review of those records revealed that of 25 individuals over 4 generations who were considered affected, 15 (60%) had cataract and glaucoma, 9 had cataract without glaucoma, and a 24-year-old woman had only persistent pupillary membrane. In addition, a 7-year-old boy, whose twin brother had unilateral cataract, was undiagnosed, and an 8-year-old girl who did not undergo genetic testing had infantile glaucoma without cataract, as well as anterior segment dysgenesis, megalocornea, corectopia, and persistent pupillary membrane. Three patients had persistent pupillary membrane, and 3 patients had retinal detachment. All family members with cataract had visually significant lens opacities and underwent lens extraction. Cataract was usually bilateral, and age at diagnosis ranged from birth to 35 years, with age at first surgery ranging from 4 to 40 years. Slit-lamp images of cataracts were not available; however, opacities had been described as punctate cortical in 1 patient and posterior subcapsular in another. A diagnosis of glaucoma was made based on significantly elevated intraocular pressure (greater than 30 mmHg) and in some cases was accompanied by visual field and/or optic nerve abnormalities; age at diagnosis ranged from birth into the fifth decade.

The transmission pattern of CTRCT50 in a large 5-generation family reported by Bennett et al. (2014) was consistent with autosomal dominant inheritance.

In affected members of a large 5-generation family with autosomal dominant cataract with or without glaucoma, who were negative for mutation in genes encoding ocular transcription factors and other candidate genes, Bennett et al. (2014) performed genomewide linkage analysis and detected significant evidence of linkage on chromosome 9q. Haplotype analysis defined a 46-Mb common disease interval spanning the pericentric region that cosegregated with disease in all affected relatives. After analysis of recombination events, the authors narrowed the disease interval to a 39.7-Mb interval between markers rs2073478 and D9S284, noting that it excluded the adjacent locus for autosomal recessive pulverulent cataract (CTRCT26; 605749) and the cataract (CTRCT36; 613887)-associated gene TDRD7 (611258).

In affected members of a large 5-generation family autosomal dominant cataract with or without glaucoma mapped to chromosome 9q, Bennett et al. (2014) performed exome sequencing and identified a heterozygous missense mutation in the TRPM3 gene (I65M; 608961.0002). The variant segregated fully with disease in the family and was not found in 192 unrelated controls or in the 1000 Genomes Project or EVS databases.

Using CRISPR/Cas9 gene editing technology, Zhou et al. (2021) generated knock-in mice with the TRPM3 cataract-associated I65M mutation (608961.0002) and compared them to Trpm3-null mice, noting that the null mice exhibited only mild impairment of lens growth, whereas Trpm3 M/M homozygotes developed severe progressive anterior pyramid-like cataract with microphthalmia. In addition, heterozygous Trpm3 I/M and hemizygous Trpm3 M/- mutants developed anterior pyramidal cataract with delayed onset, consistent with a semidominant lens phenotype. Histochemical staining revealed abnormal accumulation of calcium phosphate-like deposits and collagen fibrils in Trpm3-mutant lenses, and immunoblotting detected increased alpha-II-spectrin (SPTAN1; 182810) cleavage products consistent with calpain (see 114220) hyperactivation. Immunofluorescence confocal microscopy of Trpm3-M/M mutant lenses revealed fiber cell membrane degeneration that was accompanied by accumulation of alpha-smooth muscle actin (see 102620)-positive myofibroblast-like cells and macrosialin (CD68; 153634)-positive macrophage-like cells. The authors concluded that Trpm3 deficiency impairs lens growth but not lens transparency, and that Trpm3 dysfunction results in progressive lens degeneration and calcification, coupled with profibrotic and immune cell responses.