Alternative titles; symbols
HGNC Approved Gene Symbol: VSX2
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:74,239,449-74,262,738 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Microphthalmia with coloboma 3 | 610092 | Autosomal recessive | 3 |
| Microphthalmia, isolated 2 | 610093 | Autosomal recessive | 3 |
HOX10 encodes a developmentally regulated homeobox originally identified by De Chen et al. (1989) on the basis of its relatively abundant, retina-specific expression. Liu et al. (1994) cloned a mouse Chx10 cDNA. Percin et al. (2000) cloned a human CHX10 cDNA encoding a deduced 361-amino acid polypeptide with 97% overall identity to mouse Chx10 and complete identity in the homeodomain and CVC domain. In situ hybridization to human fetal retinal sections detected CHX10 expression in retinal neuroblasts at all stages examined. Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina.
Percin et al. (2000) determined that the CHX10 gene contains at least 5 exons.
By study of somatic cell hybrids, De Chen et al. (1989) mapped the HOX10 gene, which they called RET1, to chromosome 14. De Chen et al. (1990) sublocalized the gene to 14q24.3 by in situ hybridization. This placed HOX10 close to FOS (164810) and proximal to alpha-1-antitrypsin (107400). De Chen et al. (1990) mapped the mouse homolog to the distal part of mouse chromosome 12 by linkage analysis.
Rod-derived cone viability factor (RDCVF) is a retinal trophic factor encoded by the NXNL1 gene (608791). RDCVF expression is lost after rod degeneration in the first phase of retinitis pigmentosa (RP; 268000), and this loss has been implicated in the more clinically significant secondary cone degeneration that often occurs. Reichman et al. (2010) identified the homeodomain proteins CHX10/VSX2, VSX1 (605020), and PAX4 (167413), as well as the zinc finger protein SP3 (601804), as factors that could stimulate both the mouse and human NXNL1 promoter. In addition, CHX10/VSX2 bound to the NXNL1 promoter in vivo. Rdcvf was expressed in the inner as well as the outer retina of mice. The loss of rods in the rd1 mouse, a model of retinitis pigmentosa, was associated with decreased expression of Rdcvf by inner retinal cells as well as by rods. Reichman et al. (2010) proposed an alternative therapeutic strategy aimed at recapitulating RDCVF expression in the inner retina, where cell loss is not significant, to prevent secondary cone death and central vision loss in patients suffering from retinitis pigmentosa.
Percin et al. (2000) reported the mapping of a human microphthalmia locus on 14q24.3, the cloning of CHX10 at this locus, and the identification of recessive CHX10 mutations in 2 families with nonsyndromic microphthalmia, cataracts, and severe abnormalities of the iris (see 610092). In affected individuals from 2 unrelated families, a highly conserved arginine residue in the DNA-recognition helix of the homeodomain was replaced by glutamine or proline (R200Q, 142993.0001, and R200P, 142993.0002), respectively. Identification of the CHX10 consensus DNA binding sequence (TAATTAGC) allowed the authors to demonstrate that both mutations severely disrupted CHX10 function. The strong conservation in vertebrates of the CHX10 sequence, pattern of expression, and loss-of-function phenotypes demonstrated the evolutionary importance of the genetic network through which this gene regulates eye development.
Using linkage analysis followed by sequencing of the CHX10 gene in 2 consanguineous Arab families with isolated microphthalmia/clinical anophthalmia (MCOP2; 610093) and a Jewish Syrian family with microphthalmia/clinical anophthalmia with colobomas (MCOPCB3; 610092), Bar-Yosef et al. (2004) identified homozygosity for 3 mutations: an R227W substitution in exon 4 (142993.0003), an approximately 4-kb deletion encompassing exon 3 (142993.0004), and a splice site G-to-A transition in intron 1 (142993.0005), respectively.
In affected individuals from 2 consanguineous families from Qatar with microphthalmia and cloudy corneas (610093), Faiyaz-Ul-Haque et al. (2007) identified homozygosity for the R200P mutation (142993.0002).
McInnes et al. (1994) demonstrated that the Chx10 gene in the mouse is the site of an ochre stop mutation (UAA) in the 'ocular retardation,' or(J), mouse. The 'or' mutation causes microphthalmia, progressive destruction of the retina, and absence of the optic nerve. McInnes et al. (1994) demonstrated homozygosity for a tyr29-to-ter mutation. They suggested that CHX10 mutations may cause microphthalmia in man.
Burmeister et al. (1996) found that a null mutation in the Chx10 gene was responsible for the phenotype in mice with ocular retardation, a microphthalmia phenotype described by Truslove (1962). Burmeister et al. (1996) demonstrated that mice carrying the 'or' allele have a premature stop codon in the homeobox of the Chx10 gene, a gene expressed at high levels in uncommitted retinal progenitor cells and mature bipolar cells. Homozygotes for the 'or' allele showed no detectable CHX10 protein in the retinal neuroepithelium. The results indicated that Chx10 is an essential component in the network of genes required for the development of the mammalian eye.
Wellik and Capecchi (2003) generated mice in which all members of the Hox10 and/or Hox11 (186770) paralogous group are disrupted and showed that these genes are global regulators of the lumbosacral region of the axial skeleton and are integral in patterning principal limb elements. In the absence of Hox10 function, no lumbar vertebrae are formed. Instead, ribs project from all posterior vertebrae, extending caudally from the last thoracic vertebrae to beyond the sacral region. In the absence of Hox11 function, sacral vertebrae are not formed and instead these vertebrae assume a lumbar identity. The redundancy among these paralogous family members is so great that this global aspect of Hox patterning is not apparent in mice that are mutant for 5 of the 6 paralogous alleles.
Rutherford et al. (2004) examined how neuronal development in the mouse retina was affected by the absence of the Chx10 transcription factor. They found that delay of the normal temporal expression of genes essential for photoreceptor disc morphogenesis led to failure of correct rod and cone outer segment formation in the homozygous Chx10 null mouse retina. In addition, the absence of Chx10 appeared to affect the development of late-born cells more than that of early-born cells, in that a low number of rods developed, whereas formation of ganglion, amacrine, and cone cells was relatively unaffected.
In 2 affected members of a consanguineous kindred from Turkey with bilateral microphthalmia, congenital cataracts, and bilateral inferior colobomas of the iris (see 610092), Percin et al. (2000) identified an arg200-to-gln (R200Q) missense mutation of the CHX10 gene due to homozygosity for a G-to-A transition. Four members were affected; the abnormalities in the proband at 9 months of age and in the other affected subject available for study at age 49 years were strictly ocular. Neither had light perception.
In a 2-month-old child with bilateral microphthalmia, congenital cataracts, and no pupillary aperture (see 610092), born of clinically normal consanguineous parents, Percin et al. (2000) identified homozygosity for a 599G-A transition in the CHX10 gene, resulting in an arg200-to-pro (R200P) substitution. In addition to the ocular anomalies, the child had undescended testes.
In 6 affected individuals from 2 consanguineous families from Qatar with isolated microphthalmia (MCOP2; 610093) and cloudy corneas, Faiyaz-Ul-Haque et al. (2007) identified homozygosity for a 599G-C transversion in exon 4 of the CHX10 gene, resulting in an R200P substitution in the DNA binding domain. Unaffected parents were heterozygous for the mutation.
In affected members of a consanguineous Arab family with isolated microphthalmia/clinical anophthalmia (MCOP2; 610093), Bar-Yosef et al. (2004) identified homozygosity for a c.1237G-A transition in exon 4 of the CHX10 gene, resulting in an arg227-to-trp substitution in the CVC domain. The authors noted that this arginine residue is conserved in all known CHX10 homologs as well as in the CVC domains of related genes.
In affected members of a consanguineous Arab family previously reported by Kohn et al. (1988) with isolated severe bilateral microphthalmia/clinical anophthalmia (MCOP2; 610093), Bar-Yosef et al. (2004) identified homozygosity for an approximately 4-kb deletion encompassing exon 3 of the CHX10 gene, thus abolishing both the homeobox domain and the CVC domain. One affected member also had tracheoesophageal fistula and mild right hydronephrosis, which the authors stated were 'undoubtedly unrelated to the microphthalmia.'
In affected members of a consanguineous Jewish Syrian family with microphthalmia/clinical anophthalmia and coloboma of the iris (MCOPCB3; 610092), Bar-Yosef et al. (2004) identified homozygosity for a G-to-A transition in the last base of the first CHX10 intron, predicted to abolish the donor-acceptor site at the intron-exon junction.
Bar-Yosef, U., Abuelaish, I., Harel, T., Hendler, N., Ofir, R., Birk, O. S. CHX10 mutations cause non-syndromic microphthalmia/anophthalmia in Arab and Jewish kindreds. Hum. Genet. 115: 302-309, 2004. [PubMed: 15257456] [Full Text: https://doi.org/10.1007/s00439-004-1154-2]
Burmeister, M., Novak, J., Liang, M.-Y., Basu, S., Ploder, L., Hawes, N. L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V. I., Roderick, T. H., Taylor, B. A., Hankin, M. H., McInnes, R. R. Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genet. 12: 376-384, 1996. [PubMed: 8630490] [Full Text: https://doi.org/10.1038/ng0496-376]
De Chen, J., Bapat, B., Bascom, R., Willard, H., Gallie, B., McInnes, R. R. Identification of a developmentally regulated human retinal homeobox gene. (Abstract) Am. J. Hum. Genet. 45: A111, 1989.
De Chen, J., Ploder, L., Collins, L., Thorner, P., Kalnins, V., Duncan, A., Taylor, B., McInnes, R. R. Chromosomal sublocalization and cellular expression of the retinal homeobox gene HOX10. (Abstract) Am. J. Hum. Genet. 47: A102, 1990.
Faiyaz-Ul-Haque, M., Zaidi, S. H. E., Al-Mureikhi, M. S., Peltekova, I., Tsui, L.-C., Teebi, A. S. Mutations in the CHX10 gene in nonsyndromic microphthalmia/anophthalmia patients from Qatar. Clin. Genet. 72: 164-166, 2007. [PubMed: 17661825] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00846.x]
Kohn, G., El Shawwa, R., El Rayyes, E. Isolated 'clinical anophthalmia' in an extensively affected Arab kindred. Clin. Genet. 33: 321-324, 1988. [PubMed: 3378363]
Liu, I. S. C., Chen, J., Ploder, L., Vidgen, D., van der Kooy, D., Kalhius, V. I., McInnes, R. R. Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13: 377-393, 1994. [PubMed: 7914735] [Full Text: https://doi.org/10.1016/0896-6273(94)90354-9]
McInnes, R. R., Basu, S., Novak, J., Ploder, L., Liang, M.-Y., Hawes, N., Taylor, B., Roderick, T., Goldman, D., Hankin, M., Burmeister, M. The ocular retardation (orJ) mouse has an ochre mutation in the homeobox gene Chx10: direct evidence for Chx10 as a major determinant of retinal development. (Abstract) Am. J. Hum. Genet. 55 (suppl.): A3, 1994.
Percin, E. F., Ploder, L. A., Yu, J. J., Arici, K., Horsford, D. J., Rutherford, A., Bapat, B., Cox, D. W., Duncan, A. M. V., Kalnins, V. I., Kocak-Altintas, A., Sowden, J. C., Traboulsi, E., Sarfarazi, M., McInnes, R. R. Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nature Genet. 25: 397-401, 2000. [PubMed: 10932181] [Full Text: https://doi.org/10.1038/78071]
Reichman, S., Kalathur, R. K. R., Lambard, S., Ait-Ali, N., Yang, Y., Lardenois, A., Ripp, R., Poch, O., Zack, D. J., Sahel, J.-A., Leveillard, T. The homeobox gene CHX10/VSX2 regulates RdCVF promoter activity in the inner retina. Hum. Molec. Genet. 19: 250-261, 2010. [PubMed: 19843539] [Full Text: https://doi.org/10.1093/hmg/ddp484]
Rutherford, A. D., Dhomen, N., Smith, H. K., Sowden, J. C. Delayed expression of the Crx gene and photoreceptor development in the Chx10-deficient retina. Invest. Ophthal. Vis. Sci. 45: 375-384, 2004. [PubMed: 14744875] [Full Text: https://doi.org/10.1167/iovs.03-0332]
Truslove, G. M. A gene causing ocular retardation in the mouse. J. Embryol. Exp. Morph. 10: 652-660, 1962. [PubMed: 13994395]
Wellik, D. M., Capecchi, M. R. Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science 301: 363-367, 2003. [PubMed: 12869760] [Full Text: https://doi.org/10.1126/science.1085672]