Alternative titles; symbols
HGNC Approved Gene Symbol: GJA8
Cytogenetic location: 1q21.2 Genomic coordinates (GRCh38): 1:147,902,795-147,914,486 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.2 | Cataract 1, multiple types | 116200 | Autosomal dominant | 3 |
Gap junctions are made up of 2 interacting hemichannels that form communicating channels between neighboring cells. Each hemichannel contains 6 connexin subunits. GJA8 is a connexin of the ocular lens, where gap junctions maintain ionic and water balance and the transparency and optical properties of the lens (summary by Nielsen et al., 2003).
In the mammalian lens fiber cell membrane, 4 proteins (or their metabolic products) make up the vast majority of the total transmembrane proteins in the lens: MP19 (154045), MP26 (154050), MP46, and MP70. Church et al. (1995) isolated and characterized a human genomic clone containing the complete coding region of lens intrinsic membrane protein MP70, or connexin-50 gap junction protein. The 1,299-bp coding region for this gene encodes a protein of 48,171 Da containing 4 transmembrane domains. The human coding region demonstrates 86% identity with the mouse Cx50 at the nucleotide level and 89% identity at the protein level. Northern blot analysis suggests that human MP70 is probably expressed only in the lens.
Using Chinese hamster-human somatic cell hybrid panels, Church et al. (1995) demonstrated that the human MP70 gene segregates with complete concordancy with human chromosome 1. They suggested that the MP70 gene may be a candidate gene for a heritable cataract, since zonular pulverulent cataract (CZP1; 116200) had previously been assigned to the long arm of this chromosome.
Using a panel of somatic cell hybrids and DNAs from the European Collaborative Interspecific Backcross, Kerscher et al. (1995) mapped the Gja8 locus to mouse chromosome 3, 11.9 +/- 5.0 cM distal to D3Mit22. This is in a region that shows conserved synteny with proximal 1q in the human.
By fluorescence in situ hybridization, Geyer et al. (1997) mapped the GJA8 gene to 1q21.1.
Fiber cells of the lens are interconnected by an extensive network of gap junctions containing alpha-3 (Cx46; 121015) and alpha-8 connexins. To determine the contribution of these connexins to lens function, Gong et al. (1998) used impedance techniques to study cell-to-cell coupling in lenses from homozygous Cx46 knockout, heterozygous Cx46 knockout, and wildtype mice. Western blots and immunofluorescence data indicated that Cx50 remained at similar levels in the 3 classes of lenses, whereas Cx46 was approximately 50% of the normal level in the heterozygous lenses and absent from the homozygous knockout lenses. Moreover, the data from homozygous normal lenses suggested that a cleavage of connexins occurs abruptly between the peripheral shell of differentiating fibers and the inner core of mature fibers. The appearance of the cleaved connexins was correlated to a change in the coupling conductance. In homozygous knockout lenses, the coupling conductance of mature fibers was zero, and these fibers were depolarized by about 30 mV from normal. The differentiating fibers remained coupled, but the conductance was reduced to 30 to 35% of normal. However, the gap junctions in the differentiating fibers of homozygous Cx46 knockout lenses remained sensitive to pH. Gong et al. (1998) concluded that Cx46 is necessary for the coupling of central fibers to peripheral cells, and that this coupling is essential for fiber cell homeostasis because uncoupled mature fibers depolarize and subsequently become opaque, forming a nuclear cataract.
Using coimmunoprecipitation analysis, Nielsen et al. (2003) found that Cx46 and Cx50 interacted with the tight junction protein Zo1 (TJP1; 601009) in mouse lens fiber cells. Mutation analysis revealed that the second PDZ domain of Zo1 interacted with C-terminal isoleucines of Cx46 and Cx50.
In 2 distantly related branches of an 8-generation English kindred known as 'Ev.' with zonular pulverulent cataract (116200) that had been shown to segregate with the Duffy blood group locus on 1q (Renwick and Lawler, 1963), Shiels et al. (1997, 1998) demonstrated linkage to a 20.6-cM interval between markers D1S2746 and D1S2771. Sequencing of the entire protein coding region of the GJA8 gene revealed a missense mutation (P88S; 600897.0001) that was not found in 50 unrelated control chromosomes.
Berry et al. (1999) studied 10 affected and 5 unaffected members of a family of Pakistani origin segregating autosomal dominant congenital nonprogressive zonular nuclear pulverulent cataract and found linkage to the CZP1 locus; analysis of the GJA8 gene revealed heterozygosity for a missense mutation (E48K; 600897.0002) in affected individuals that was not found in 100 ethnically matched control chromosomes.
In a 3-generation Russian family with zonular pulverulent cataract, Polyakov et al. (2001) identified a missense mutation in the GJA8 gene (I247M; 600897.0003).
In a 4-generation Iranian family segregating autosomal dominant progressive congenital nuclear cataract (116200), Willoughby et al. (2003) identified heterozygosity for a missense mutation in the GJA8 gene (R23T; 600897.0004). Affected family members had bilateral congenital cataracts that progressed and required surgery in the second and third decades due to dense fetal/embryonal nuclear cataract. No other systemic or ocular defects were present, including microcornea or microphthalmia.
Devi and Vijayalakshmi (2006) analyzed the GJA8 gene in 60 unrelated Indian patients with congenital or early childhood cataract, and identified 2 different missense mutations (600897.0005 and 600897.0006, respectively) in 2 probands from families with cataract and microcornea (116200).
In a Danish family segregating autosomal dominant stellate nuclear cataract and microcornea, Hansen et al. (2007) identified heterozygosity for a missense mutation in the GJA8 gene (600897.0008).
Arora et al. (2008) sequenced the GJA8 gene in 150 families with inherited cataract and identified heterozygosity for a missense mutation (600897.0007) in a 2-generation Caucasian family segregating autosomal dominant congenital nuclear pulverulent cataract (116200). He et al. (2011) identified the same mutation in affected members of a 6-generation Chinese family segregating nuclear cataract as well as in 1 unaffected member of the family, suggesting incomplete penetrance.
White et al. (1998) generated mice with a targeted deletion of the Cx50 gene. Cx50-null mice exhibited microphthalmia and nuclear cataracts. At postnatal day 14, the eyes of Cx50 knockout mice weighed 32% less than those of controls, whereas lens mass was reduced by 46%. Cx50-knockout lenses also developed zonular pulverulent cataracts, and lens abnormalities were detected by postnatal day 7. Deletion of Cx50 did not alter the amount or distribution of Cx46 or Cx43 (121014), a component of lens epithelial junctions. In addition, intercellular passage of tracers revealed the persistence of communication between all cell types in the Cx50-knockout lens.
White (2002) targeted replacement of Cx50 with Cx46 by genetic knockin. This replacement corrected defects in cellular differentiation and prevented cataracts, but did not restore normal growth. White (2002) concluded that intrinsic properties of Cx50 are required for cellular growth, whereas nonspecific restoration of communication by Cx46 maintains differentiation.
Chang et al. (2002) mapped an autosomal semi-dominant cataract (Lop10) mutation (Runge et al., 1992) to mouse chromosome 3 and identified a gly22-to-arg (G22R) mutation in Gja8. The alpha-8 G22R isoform is a loss-of-function mutant for alpha-8, as well as a dominant mutation for reducing the phosphorylated forms of alpha-3 connexin in vivo. Double mutant offspring between Lop10 and the Gja3-tm1 (alpha-3 -/-) mice (Gong et al., 1997) showed relatively normal lens cortical fibers compared to the Lop10 mice. The authors concluded that a functional impairment of endogenous alpha-3 connexin is therefore partly responsible for cellular phenotypes in the Lop10 mice.
In an English kindred ('Ev.') with zonular pulverulent cataract (CTRCT1; 116200) linked to the Duffy blood group locus on chromosome 1q, Shiels et al. (1997, 1998) demonstrated a C-to-T transition in the protein-coding region of the GJA8 gene. The mutation introduced a novel MnlI restriction enzyme site. Restriction analysis confirmed that the change was present only in affected members of the pedigree; it was not detected in 50 unrelated normal chromosomes. The mutation in this family was located at nucleotide 262 and resulted in a nonconservative substitution of serine for proline at codon 88.
Shiels et al. (1998) traced this historic family using the registers at Moorfields Eye Hospital and Great Ormond Street Hospital, both in London. Referred to as the Ev. cataract family, it had first been described, in 4 generations, by Nettleship (1909) and then, in 6 generations, by Renwick and Lawler (1963), who showed linkage to Duffy blood group. Although all of the affected family members traced in the study of Shiels et al. (1998) had undergone lens surgery, hospital records confirmed that the cataract usually either was present at birth or developed in infancy and that there was no family history of other ocular or systemic abnormalities. The cataract must be distinguished from the Coppock cataract, which was described in a family of that name by Nettleship and Ogilvie (1906) and has been shown to be due to mutation in a crystallin gene (see 604307). The Coppock cataract is confined to the tiny embryonic lens, whereas the 'Ev.' cataract involves a larger fetal lens, which is more compatible in size to the nucleus of the adult lens.
In 10 affected members of a 3-generation Pakistani family with zonular nuclear pulverulent cataract linked to chromosome 1q (CTRCT1; 116200), Berry et al. (1999) identified a 142G-A transition in the GJA8 gene, resulting in a glu48-to-lys (E48K) substitution. The mutation was not found in 100 ethnically matched control chromosomes.
In a mother and son from a 3-generation Russian family with zonular pulverulent cataract (CTRCT1; 116200), Polyakov et al. (2001) identified heterozygosity for a 741T-G transversion, resulting in an ile247-to-met (I247M) substitution in the last intracellular domain. The mutation was not found in unaffected members of the family or in 25 unrelated controls.
In affected members of a 4-generation Iranian family segregating autosomal dominant progressive congenital nuclear cataract (CTRCT1; 116200), Willoughby et al. (2003) identified heterozygosity for a 68G-C transversion in the GJA8 gene, resulting in an arg23-to-thr (R23T) substitution at a highly conserved residue within the cytoplasmic N-terminal region at the membrane-cytoplasm boundary of the first transmembrane (M1) domain. The mutation was not found in unaffected family members or in 100 controls of mixed ethnicity or in 52 ethnically matched controls.
In an Indian father and daughter with congenital cataract and microcornea (CTRCT1; 116200), Devi and Vijayalakshmi (2006) identified heterozygosity for a 131T-A transversion in the GJA8 gene, resulting in a val44-to-glu (V44E) substitution in the first transmembrane domain. The daughter had surgery at 3 months of age for total lens opacification; her father, who had undergone cataract surgery at age 3 years, was noted to have increased axial lengths suggestive of mild myopia.
In 3 members of an Indian family with congenital cataract and microcornea (CTRCT1; 116200), Devi and Vijayalakshmi (2006) identified heterozygosity for a 593G-A transition in the GJA8 gene, resulting in an arg198-to-gln (R198Q) substitution in the second extracellular loop. The proband was a 7-year-old boy with posterior subcapsular cataract for which he underwent surgery at 4 years of age; he also had increased axial length suggestive of mild myopia. His 32-year-old mother, who was diagnosed with high myopia, had undergone cataract extraction at 10 years of age; and his maternal grandfather had cataract extraction at 22 years of age.
In 4 affected members of a 2-generation family segregating autosomal dominant congenital nuclear pulverulent cataract (CTRCT1; 116200), Arora et al. (2008) identified heterozygosity for a 139G-A transition in the coding region of the GJA8 gene, resulting in an asp470-to-asn (D47N) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in 156 ethnically matched controls. Functional studies in paired oocytes injected with D47N-mutant Cx50 showed no detectable intercellular conductance; coexpression of D47N-mutant Cx50 did not inhibit gap junctional conductance of wildtype Cx50. In transiently transfected HeLa cells, wildtype Cx50 localized to appositional membranes and within the perinuclear region, whereas D47N-mutant Cx50 showed no immunostaining at appositional membranes and immunoreactivity was confined to the cytoplasm.
In a 6-generation Chinese family segregating nuclear cataract, He et al. (2011) identified the D47N mutation in heterozygous state in all affected members and in 1 unaffected member, suggesting incomplete penetrance. The mutation led to loss of function of the protein.
In a Danish mother and her 3 children with stellate nuclear cataract and microcornea (CTRCT1; 116200), Hansen et al. (2007) identified heterozygosity for a c.565C-T transition in exon 2 of the GJA8 gene, resulting in a pro189-to-leu (P189L) substitution at a highly conserved residue in the second extracellular region. The mutation was not found in 170 ethnically matched volunteers. Examination of the 4 affected family members showed star-shaped nuclear opacities with a whitish central core; corneas were 10 mm in diameter.
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