Disease relevance of CHX10

• CHX10 blocked TATA-containing and TATA-less promoters, repressed at a distance, and inhibited a complex enhancer positioned upstream or downstream of the reporter gene, whereas retinoblastoma protein (RB) inhibited the downstream enhancer only [1].
• We report here the mapping of a human microphthalmia locus on chromosome 14q24.3, the cloning of CHX10 at this locus and the identification of recessive CHX10 mutations in two families with non-syndromic microphthalmia (MIM 251600), cataracts and severe abnormalities of the iris [2].
• CHX10 mutations cause non-syndromic microphthalmia/ anophthalmia in Arab and Jewish kindreds [3].
• It has been previously shown that mutations in a particular nucleotide in CHX10 are associated with an autosomal recessive syndrome of microphthalmia/anophthalmia with iris colobomas and cataracts in two families [3].
• The frequency of GFP(+) cells immunoreactive with the ganglion cell-specific antibody RA4 was unchanged by Chx10, but was increased twofold by Pax6 [4].

High impact information on CHX10

• Human CHX10 is expressed in progenitor cells of the developing neuroretina and in the inner nuclear layer of the mature retina [2].
• The strong conservation in vertebrates of the CHX10 sequence, pattern of expression and loss-of-function phenotypes demonstrates the evolutionary importance of the genetic network through which this gene regulates eye development [2].
• Human microphthalmia associated with mutations in the retinal homeobox gene CHX10 [2].
• However, both CHX10 (14q24.3), mutations of which give rise to CMIC in mouse models, and OTX2 (14q21-22) can be excluded as candidates for autosomal recessive congenital microphthalmia (arCMIC), since they map outside the critical disease region defined by recombination events [5].
• Previous studies have demonstrated that HOX-9 and HOX-10 paralog proteins are unique among HOX homeodomain proteins in their capacity to form in vitro cooperative DNA binding complexes with either the PBX or MEIS protein [6].

Chemical compound and disease context of CHX10

• Putative genes of anophthalmia and microphthalmia reported to date include PAX6 (Glaser T et al 1994) and CHX10 (Ferda Percin E et al 2000) [7].

Biological context of CHX10

• CHX10 is required first for retinal progenitor cell proliferation and later for bipolar cell differentiation, whereas VSX1 is important in the terminal differentiation of a subset of bipolar cells [1].
• Mutations in the related human CHX10 gene cause microphthalmia in a subset of families, and, therefore, the RINX gene is a candidate for this phenotype in another subset of patients [8].
• PURPOSE: The Chx10 homeobox gene is expressed in neural progenitor cells during retinal development [9].
• DNA footprinting assays revealed footprints over the primary transcription startpoint and the RET1-like and TATA box regions [10].
• Electrophoretic mobility shift assays generate a retina-specific bandshift using a 322-bp fragment containing the putative promoter region or a multimer of the RET1-like site [10].

Anatomical context of CHX10

• CHX10 targets a subset of photoreceptor genes [11].
• Ret1 mRNA first appears during early somitogenesis in the presumptive brain, spinal cord and excretory system [12].
• Ret1 transcripts are also expressed in subsets of neural crest cells and cranial ganglia as well as in the enteric nervous system [12].
• We postulate that this disorder is related to misexpression of one or more distal HOX genes, potentially HOX10 or HOX11, leading to abnormal induction and proliferation of caudal mesenchyme [13].

Other interactions of CHX10

• VSX1 contains closely related homeo and CVC domains and, like CHX10, also repressed transcription [1].
• A total of 84/122 of the MAC cases were screened for mutations in the coding regions of PAX6, CHX10, and SIX3 [14].
• RESULTS: Nonphotoreceptor neurons increased threefold with Chx10 and almost sixfold with Pax6, compared with cells transfected with lacZ [4].
• Ophthalmologic manifestations, fundus photographs, ultrasonographic (US) assessment, electroretinography (ERG), fluorescein retinal angiography (FA), Goldmann kinetic perimetry (GKP), and optical coherence tomography (OCT), as well as mutational status of MFRP and CHX10 genes in genomic DNA [15].
• Physical mapping of CHX10, ALDH6A1, and ABCD4 on bovine chromosome 10q34 [16].

References