Alternative titles; symbols
ORPHA: 91492; DO: 0110253;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.11 | Cataract 14, multiple types | 601885 | Autosomal dominant | 3 | GJA3 | 121015 |
A number sign (#) is used with this entry because of evidence that multiple types of cataract (CTRCT14) are caused by heterozygous mutation in the gene encoding gap junction protein alpha-3 (GJA3; 121015), also known as connexin-46 (CX46), on chromosome 13q12.
Mutations in the GJA3 gene have been found to cause multiple types of cataract, which have been described as zonular pulverulent, posterior polar, nuclear coralliform, embryonal nuclear, and Coppock-like.
The preferred title/symbol for this entry was formerly 'Cataract, Zonular Pulverulent 3; CZP3.'
Rees et al. (2000) described a 4-generation family segregating autosomal dominant, morphologically homogeneous 'zonular pulverulent' cataracts. The cataract was bilateral and consisted of a central pulverulent (dust-like) opacity affecting the embryonal, fetal, and infantile nucleus of the lens. It was surrounded by snowflake-like opacities of varying density in the anterior and posterior cortical region of the lens. The eye examination was otherwise normal and no systemic abnormalities were detected.
Burdon et al. (2004) reported a large Australian pedigree with autosomal dominant cataract in which the phenotype was a faint lamellar nuclear opacity surrounding pulverulent nuclear opacities, some with fine gold dots or haze and some with needle-like peripheral (cortical) riders. The median age of diagnosis was 5 years, but the patients in the 2 most recent generations were diagnosed at 6 months to 2 years of age. No other ocular or systemic abnormalities were noted.
Li et al. (2004) studied 12 affected members of a large 5-generation Chinese family segregating bilateral congenital cataracts, only 2 of whom had not undergone cataract extraction prior to examination. In those 2 patients, cataract was bilateral and consisted of a central pulverulent opacity involving the embryonal, fetal, and infantile nucleus of the lens.
Using transmission electron microscopy to examine the lens from the proband of a large 4-generation Chinese family in which 20 members had nuclear pulverulent and posterior polar opacities, Yao et al. (2011) observed the presence of substantial abnormal 0.5- to 1-micrometer globular or vesicular structures in the cytoplasm of most lens fiber cells.
Zhang et al. (2012) studied a large 4-generation Chinese family in which 11 individuals had bilateral congenital cataracts, 9 of whom had undergone cataract extraction prior to examination. The remaining 2 patients presented with almost identical cataracts consisting of dense coralliform opacities in the central or nuclear region of the lens and fine blue dust-like opacities in the cortical zone.
Wang and Zhu (2012) described a 7-year-old Chinese boy who was diagnosed at 4 years of age with bilateral nuclear cataract, in whom slit-lamp examination revealed dense opacities in the embryonal nucleus. Medical records showed that 5 additional family members, including his mother and maternal grandfather, had been diagnosed with bilateral nuclear cataract and had undergone cataract extraction. There were no other ocular or systemic abnormalities in the family.
Zhang et al. (2012) studied 24 affected and 22 unaffected members of a large 5-generation Chinese family segregating autosomal dominant Coppock-like cataract with no other ocular or systemic abnormalities. Affected individuals presented with a bilateral granular opacity in the center of the lens; upon examination, the cataract appeared as a circular spotted disc in the center of the lens. Slit-lamp examination showed a small spotted or granular opacity that appeared to involve only the embryonal nucleus. Most patients experienced decreased visual acuity around 7 to 8 years of age, with some requiring cataract surgery in childhood.
The transmission pattern of CTRCT14 in the families reported by Mackay et al. (1999) was consistent with autosomal dominant inheritance.
Mackay et al. (1997) reported linkage of a locus for dominant zonular pulverulent cataract (CZP3) to chromosome 13. They performed linkage analysis using microsatellite markers in a 5-generation English pedigree and obtained maximum lod scores of 4.06 (theta = 0) for the marker D13S175 and 5.75 (theta = 0) for the marker S13S1236. Multipoint analysis gave a maximum lod of 6.62 at marker D13S175. Haplotype data suggested that the CZP3 locus probably lies in the centromeric region of chromosome 13, close to the gene for lens connexin-46 (121015).
Hejtmancik (1998) presented a table of 9 loci, including this one, which had been implicated in nonsyndromal cataract and mapped to specific chromosomal sites. Eight animal models of cataract in which molecular defects had been identified were also tabulated.
In a large Australian pedigree segregating autosomal dominant cataract, Burdon et al. (2004) obtained a lod score of 2.96 at D13S1236 (theta = 0.04).
In a large 5-generation Chinese family with nuclear pulverulent cataract, Li et al. (2004) performed linkage analysis and obtained a lod score of 3.61 at D13S175. Two-point linkage and haplotype analysis confined the minimal disease haplotype to an interval at 13q11-q13 involving markers D13S1316, D13S175, D13S292, and D13S1243, with Zmax ranging from 0.22 to 4.26.
In a large 4-generation Chinese family with nuclear coralliform congenital cataract, Zhang et al. (2012) performed genotyping with 22 polymorphic markers around known autosomal dominant congenital cataract loci, which excluded all loci except the GJA3 gene. The 2-point lod score for D13S175 was 1.60 (theta = 0) with full penetrance; lod scores for markers D13S292 and D13S1236 were 2.51 and 2.39, respectively. Linkage and haplotype analysis for the 3 markers suggested that the GJA3 gene might be the disease-causing gene in this family.
By linkage analysis in a large 5-generation Chinese family segregating autosomal dominant Coppock-like cataract, Zhang et al. (2012) excluded known Coppock cataract-associated loci and obtained a lod score of 4.49 for marker D13S1236 (theta = 0). A maximum 2-point lod score of 5.90 was obtained at marker D13S175 (theta = 0), with lod scores greater than 3.0 for adjacent markers, including D13S1316. Haplotype analysis narrowed the critical interval to a 6.99-cM region bounded by D13S1316 and D13S1275 at 13q12.11, containing the GJA3 gene.
In affected members of 2 unrelated families with autosomal dominant zonular pulverulent cataract mapping to chromosome 13, Mackay et al. (1999) analyzed the candidate gene GJA3 and identified heterozygosity for a missense mutation (121015.0001) and a 1-bp insertion (121015.0002), respectively.
In a 4-generation family with fully penetrant autosomal dominant congenital cataracts in which linkage and haplotype studies supported localization to 13q11, Rees et al. (2000) identified a heterozygous missense mutation in the GJA3 gene (P187L; 121015.0003).
In 21 affected members of a large Australian pedigree with zonular pulverulent cataract, Burdon et al. (2004) identified heterozygosity for a mutation in the GJA3 gene (R76H; 121015.0004). The mutation, which was not found in 100 control chromosomes, was also identified in 6 unaffected members of the family. The authors stated that inheritance in the pedigree was clearly autosomal dominant, although the mutation was not fully penetrant.
By direct sequencing of the GJA3 gene in a large 5-generation Chinese family with nuclear pulverulent cataract, Li et al. (2004) identified a heterozygous missense mutation (N188T; 121015.0005) that segregated with disease and was not found in 100 unrelated controls.
In a large 4-generation Chinese family segregating autosomal dominant nuclear pulverulent and posterior polar cataract, Yao et al. (2011) sequenced the GJA3 gene and identified heterozygosity for a missense mutation (G2D; 121015.0006) in all affected individuals.
In affected members of a large 4-generation Chinese family with nuclear coralliform cataract mapping to chromosome 13q, Zhang et al. (2012) identified heterozygosity for a missense mutation in the GJA3 gene (N188I; 121015.0007) that was not found in 100 unrelated controls. Zhang et al. (2012) stated that 17 different mutations had been reported in the GJA3 gene; noting the observed inter- and intra-familial differences with respect to morphology and location of lens opacities, they suggested that these differences might be due to interaction of the background environment and/or modifier genes.
In a 3-generation Chinese family with embryonal nuclear cataract, Wang and Zhu (2012) screened 8 crystalline and 2 connexin genes and identified heterozygosity for a missense mutation in the GJA3 gene (F206I; 121015.0008) that segregated with disease and was not found in 110 ethnically matched controls.
In a large 5-generation Chinese family with Coppock-like cataract mapping to chromosome 13q12.11, Zhang et al. (2012) identified a heterozygous missense mutation in the GJA3 gene (G143R; 121015.0009) that segregated with disease in 24 affected and 22 unaffected family members and was not found in 100 unrelated controls.
Burdon, K. P., Wirth, M. G., Mackey, D. A., Russell-Eggitt, I. M., Craig, J. E., Elder, J. E., Dickinson, J. L., Sale, M. M. A novel mutation in the connexin 46 gene causes autosomal dominant congenital cataract with incomplete penetrance. J. Med. Genet. 41: e106, 2004. Note: Electronic Article. Erratum: J. Med. Genet. 42: 288 only, 2005; Erratum: J. Med. Genet. 45: 256 only, 2008. [PubMed: 15286166] [Full Text: https://doi.org/10.1136/jmg.2004.018333]
Hejtmancik, J. F. The genetics of cataract: our vision becomes clearer. (Editorial) Am. J. Hum. Genet. 62: 520-525, 1998. [PubMed: 9497271] [Full Text: https://doi.org/10.1086/301774]
Li, Y., Wang, J., Dong, B., Man, H. A novel connexin46 (GJA3) mutation in autosomal dominant congenital nuclear pulverulent cataract. Molec. Vis. 10: 668-671, 2004. [PubMed: 15448617]
Mackay, D., Ionides, A., Berry, V., Moore, A., Bhattacharya, S., Shiels, A. A new locus for dominant 'zonular pulverulent' cataract, on chromosome 13. Am. J. Hum. Genet. 60: 1474-1478, 1997. [PubMed: 9199569] [Full Text: https://doi.org/10.1086/515468]
Mackay, D., Ionides, A., Kibar, Z., Rouleau, G., Berry, V., Moore, A., Shiels, A., Bhattacharya, S. Connexin46 mutations in autosomal dominant congenital cataract. Am. J. Hum. Genet. 64: 1357-1364, 1999. [PubMed: 10205266] [Full Text: https://doi.org/10.1086/302383]
Rees, M. I., Watts, P., Fenton, I., Clarke, A., Snell, R. G., Owen, M. J., Gray, J. Further evidence of autosomal dominant congenital zonular pulverulent cataracts linked to 13q11 (CZP3) and a novel mutation in connexin 46 (GJA-3). Hum. Genet. 106: 206-209, 2000. [PubMed: 10746562] [Full Text: https://doi.org/10.1007/s004390051029]
Wang, K. J., Zhu, S. Q. A novel p.F206I mutation in Cx46 associated with autosomal dominant congenital cataract. Molec. Vis. 18: 968-973, 2012. [PubMed: 22550389]
Yao, K., Wang, W., Zhu, Y., Jin, C., Shentu, X., Jiang, J., Zhang, Y., Ni, S. A novel GJA3 mutation associated with congenital nuclear pulverulent and posterior polar cataract in a Chinese family. Hum. Mutat. 32: 1367-1370, 2011. [PubMed: 21681855] [Full Text: https://doi.org/10.1002/humu.21552]
Zhang, L., Qu, X., Su, S., Guan, L., Liu, P. A novel mutation in GJA3 associated with congenital Coppock-like cataract in a large Chinese family. Molec. Vis. 18: 2114-2118, 2012. [PubMed: 22876138]
Zhang, X., Wang, L., Wang, J., Dong, B., Li, Y. Coralliform cataract caused by a novel connexin46 (GJA3) mutation in a Chinese family. Molec. Vis. 18: 203-210, 2012. [PubMed: 22312188]