Alternative titles; symbols
HGNC Approved Gene Symbol: LIM2
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38): 19:51,379,909-51,387,974 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.41 | Cataract 19, multiple types | 615277 | Autosomal dominant; Autosomal recessive | 3 |
Mulders et al. (1988) identified a novel bovine lens-specific protein, which they designated MP17, with both phosphorylation and calmodulin-binding properties. Gutekunst et al. (1990) isolated and characterized bovine cDNA for this protein, which they designated MP19. Using the bovine cDNA, Church and Wang (1992) identified human MP19. Church and Wang (1993) determined that the MP19 gene encodes a 173-amino acid protein with a molecular mass of approximately 19.5 kD, essentially identical to that of bovine MP19. They stated that MP19 is the second most abundant intrinsic membrane protein of the lens fiber cell.
The MP19 gene contains 5 exons and spans approximately 8 kb. It has 7 Alu repeat sequences (Church and Wang, 1992).
Using a bovine cDNA clone encoding MP19, Church and Wang (1992) analyzed Southern blots of Chinese hamster-human somatic cell hybrid DNAs to assign the gene for MP19 to human chromosome 19. The assignment was confirmed using a human chromosome 19-specific genomic library.
Lieuallen et al. (1994) confirmed the assignment of the LIM2 gene to chromosome 19 and by fluorescence in situ hybridization regionalized the assignment to 19q13.4. They showed that it is within 40 kb of the electron transport flavoprotein gene (ETFB; 130410); a cosmid containing sequences from both genes was identified. Kerscher et al. (1995) mapped the Lim2 gene to mouse chromosome 7 in a region of conserved synteny with human chromosome 19.
In 3 affected sibs from an inbred Iraqi Jewish family with presenile cortical pulverulent cataract mapping to chromosome 19q (CTRCT19; 615277), Pras et al. (2002) identified a homozygous missense mutation in the LIM2 gene (F105V; 154045.0001).
Ponnam et al. (2008) screened the probands from 40 Indian families with congenital or developmental cataract for mutation in 10 candidate genes and identified homozygosity for a missense mutation in the LIM2 gene (G154E; 154045.0002) in affected members of 1 family with congenital total cataract.
In affected members of a 4-generation British family and a 3-generation Czech family segregating autosomal dominant congenital cataract, Berry et al. (2020) identified heterozygosity for a missense mutation in the LIM2 gene (R130C; 154045.0003).
In 11 affected members over 4 generations of a Chinese family with membranous cataract, Pei et al. (2020) identified heterozygosity for the previously reported R130C mutation in the LIM2 gene.
In affected individuals from 4 Chinese families with congenital cataract of various types, Wang et al. (2021) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. Haplotype analysis suggested that the mutation likely arose due to independent founder events in each family.
In a cohort of 62 patients from 51 Spanish families with nonsyndromic congenital cataract, Fernandez-Alcalde et al. (2021) screened a panel of 39 known nonsyndromic congenital cataract-associated genes and identified 11 patients from 2 families (17 and 18) who were heterozygous for the recurrent R130C mutation in the LIM2 gene. The authors also tabulated a maternally inherited heterozygous R129C mutation in LIM2 in another family (19), but clinical details were not provided for that family and the variant was listed as being of unknown significance.
In 4 affected individuals over 3 generations of a Japanese family with congenital cataract, Berry et al. (2022) identified heterozygosity for the recurrent LIM2 R130C mutation.
In the cataractous mouse mutant 'total opacity number 3' (To3), Steele et al. (1997) found that the Lim2 gene carries a single G-to-T transversion within the first coding exon. The DNA change results in the nonconservative substitution of a valine for the normally encoded glycine at amino acid 15 of the MP19 polypeptide.
Steele et al. (2000) generated transgenic mice carrying the Lim2 mutation identified in To3 mice. Mice carrying this transgene developed cataracts. Low levels of mutant mRNA produced by the transgene cassette as compared to endogenous levels of normal Lim2 mRNA indicate that the To3 mutation exerts a dominant-negative effect.
The To3 mouse shows congenital cataract caused by a valine-to-glycine substitution at position 15 (V15G) of the Lim2 gene (Steele et al., 1997). The disorder is inherited in a semidominant fashion, with both heterozygous and homozygous mice exhibiting dense opacity of the lens. Transgenic mice harboring the V15G mutation of the gene showed very similar findings.
Shiels et al. (2007) generated mice deficient in Lim2 by using a gene-trap vector to disrupt intron 3, effectively resulting in a null allele. Heterozygous Lim2 gene-trap lenses were morphologically indistinguishable from wildtype, whereas homozygous Lim2 gene-trap lenses consistently developed faint, central pulverulent cataracts. Laser imaging analysis indicated that rays passing through the peripheral cortex of the homozygous gene-trap lenses were more strongly refracted than normal, suggesting that the internal gradient refractive index of the lens was disturbed. Shiels et al. (2007) concluded that this was the first direct evidence that LIM2 plays a critical role in establishing the correct internal refractive properties of the crystalline lens.
In 3 sibs of an Iraqi Jewish family with first-cousin parents, Pras et al. (2002) identified a phe105-to-val (F105V) homozygous missense mutation in the LIM2 gene that segregated with late-onset pulverulent cortical cataract (CTRCT19; 615277).
In 4 affected members of a consanguineous Indian family with congenital total cataract (CTRCT19; 615277), Ponnam et al. (2008) identified homozygosity for a c.587G-A transition in exon 5 of the LIM2 gene, resulting in a gly154-to-glu (G154E) substitution predicted to be located within the fourth transmembrane segment of MP19. Unaffected members of the family were heterozygous for the mutation, which was not found in 75 ethnically matched controls. Ponnam et al. (2008) noted that codon 154 spans 2 exons, involving bases at the 3-prime boundary of exon 4 and the 5-prime boundary of exon 5, suggesting that the mutation might have an effect on mRNA splicing.
In affected members of a 4-generation British family and a 3-generation Czech family segregating autosomal dominant congenital cataract (CTRCT19; 615277), Berry et al. (2020) identified heterozygosity for a c.388C-T transition in exon 4 of the LIM2 gene, resulting in an arg130-to-cys (R130C) substitution within the second extracellular loop. The mutation segregated with disease in both families. The cataract type was pulverulent in the British family and nuclear in the Czech family.
In a large 4-generation Chinese family segregating autosomal dominant membranous cataract, Pei et al. (2020) identified heterozygosity for the c.388C-T transition (c.388C-T, NM_001161748.1) resulting in the R130C mutation in the LIM2 gene. Sanger sequencing confirmed the mutation, which segregated fully with disease and was not found in 100 unrelated controls or in the 1000 Genomes or ExAC databases.
In 11 affected individuals from 4 Chinese families with congenital cataract of various types, Wang et al. (2021) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The mutation segregated with disease in families 1, 2, and 4, and arose de novo in the proband in family 3. Haplotype analysis suggested that the mutation likely arose due to independent founder events in each family.
In 11 patients from 2 Spanish families (17 and 18) with congenital cataract, Fernandez-Alcalde et al. (2021) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The patients exhibited various cataract types, including lamellar, posterior polar, and nuclear.
In 4 affected individuals over 3 generations of a Japanese family with congenital cataract, Berry et al. (2022) identified heterozygosity for the recurrent R130C mutation in the LIM2 gene. The proband was a 3-year-old girl with bilateral lamellar cataract; her 2-month-old brother had sutural cataract in the left eye and lamellar opacities in the right eye.
Berry, V., Fujinami, K., Mochizuki, K., Iwata, T., Pontikos, N., Quinlan, R. A., Michaelides, M. A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family. Ophthalmic Genet. 43: 622-626, 2022. [PubMed: 35736209] [Full Text: https://doi.org/10.1080/13816810.2022.2090010]
Berry, V., Pontikos, N., Dudakova, L., Moore, A. T., Quinlan, R., Liskova, P., Michaelides, M. A novel missense mutation in LIM2 causing isolated autosomal dominant congenital cataract. Ophthalmic Genet. 41: 131-134, 2020. [PubMed: 32202185] [Full Text: https://doi.org/10.1080/13816810.2020.1737950]
Church, R. L., Wang, J. Assignment of the lens intrinsic membrane protein MP19 structural gene to human chromosome 19. Curr. Eye Res. 11: 421-424, 1992. [PubMed: 1606837] [Full Text: https://doi.org/10.3109/02713689209001795]
Church, R. L., Wang, J. The human lens fiber-cell intrinsic membrane protein MP19 gene: isolation and sequence analysis. Curr. Eye Res. 12: 1057-1065, 1993. [PubMed: 8137630] [Full Text: https://doi.org/10.3109/02713689309033503]
Fernandez-Alcalde, C., Nieves-Moreno, M., Noval, S., Peralta, J. M., Montano, V. E. F., del Pozo, A., Santos-Simarro, F., Vallespin, E. Molecular and genetic mechanism of non-syndromic congenital cataracts: mutation screening in Spanish families. Genes (Basel) 12: 580, 2021. [PubMed: 33923544] [Full Text: https://doi.org/10.3390/genes12040580]
Gutekunst, K. A., Rao, G. N., Church, R. L. Molecular cloning and complete nucleotide sequence of the cDNA encoding a bovine lens intrinsic membrane protein (MP19). Curr. Eye Res. 9: 955-961, 1990. [PubMed: 2276272] [Full Text: https://doi.org/10.3109/02713689009069931]
Kerscher, S., Church, R. L., Boyd, Y., Lyon, M. F. Mapping of four mouse genes encoding eye lens-specific structural, gap junction, and integral membrane proteins: Cryba1 (crystallin-beta-A3/A1), Crybb2 (crystallin-beta-B2), Gja8 (MP70), and Lim2 (MP19). Genomics 29: 445-450, 1995. [PubMed: 8666393] [Full Text: https://doi.org/10.1006/geno.1995.9983]
Lieuallen, K., Christensen, M., Brandriff, B., Church, R., Wang, J., Lennon, G. Assignment of the human lens fiber cell MP19 gene (LIM2) to chromosome 19q13.4, and adjacent to ETFB. Somat. Cell Molec. Genet. 20: 67-69, 1994. [PubMed: 8197479] [Full Text: https://doi.org/10.1007/BF02257488]
Mulders, J. W. M., Voorter, C. E. M., Lamers, C., de Haard-Hoekman, W. A., Montecucco, C., van de Ven, W. J. M., Bloemendal, H., de Jong, W. W. MP17, a fiber-specific intrinsic membrane protein from mammalian eye lens. Curr. Eye Res. 7: 207-219, 1988. [PubMed: 3371069] [Full Text: https://doi.org/10.3109/02713688808995750]
Pei, R., Liang, P.-F., Ye, W., Li, J., Ma, J.-Y., Zhou, J. A novel mutation of LIM2 causes autosomal dominant membranous cataract in a Chinese family. Int. J. Ophthal. 13: 1512-1520, 2020. [PubMed: 33078099] [Full Text: https://doi.org/10.18240/ijo.2020.10.02]
Ponnam, S. P. G., Ramesha, K., Tejwani, S., Matalia, J., Kannabiran, C. A missense mutation in LIM2 causes autosomal recessive congenital cataract. Molec. Vision 14: 1204-1208, 2008. [PubMed: 18596884]
Pras, E., Levy-Nissenbaum, E., Bakhan, T., Lahat, H., Assia, E., Geffen-Carmi, N., Frydman, M., Goldman, B., Pras, E. A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family. Am. J. Hum. Genet. 70: 1363-1367, 2002. [PubMed: 11917274] [Full Text: https://doi.org/10.1086/340318]
Shiels, A., King, J. M., Mackay, D. S., Bassnett, S. Refractive defects and cataracts in mice lacking lens intrinsic membrane protein-2. Invest. Ophthal. Vis. Sci. 48: 500-508, 2007. [PubMed: 17251442] [Full Text: https://doi.org/10.1167/iovs.06-0947]
Steele, E. C., Jr., Kerscher, S., Lyon, M. F., Glenister, P. H., Favor, J., Wang, J., Church, R. L. Identification of a mutation in the MP19 gene, Lim2, in the cataractous mouse mutant To3. Molec. Vision 3: 5, 1997. Note: Electronic Article. [PubMed: 9238094]
Steele, E. C., Jr., Wang, J.-H., Lo, W.-K., Saperstein, D. A., Li, X., Church, R. L. Lim2(To3) transgenic mice establish a causative relationship between the mutation identified in the Lim2 gene and cataractogenesis in the To3 mouse mutant. Molec. Vis. 6: 85-94, 2000. [PubMed: 10851259]
Wang, X., Qin, Y., Abudoukeremuahong, A., Dongye, M., Zhang, X., Wang, D., Li, J., Lin, Z., Yang, Y., Ding, L., Lin, H. Elongated axial length and myopia-related fundus changes associated with the Arg130Cys mutation in the LIM2 gene in four Chinese families with congenital cataracts. Ann. Transl. Med 9: 235, 2021. [PubMed: 33708862] [Full Text: https://doi.org/10.21037/atm-20-4275]