Alternative titles; symbols
HGNC Approved Gene Symbol: HMX1
Cytogenetic location: 4p16.1 Genomic coordinates (GRCh38): 4:8,846,076-8,871,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.1 | Oculoauricular syndrome | 612109 | Autosomal recessive | 3 |
Proteins encoded by homeobox genes function as transcription factors capable of binding DNA. Structural analysis of homeodomains indicate that these proteins form a helix-turn-helix motif, with the third helix serving as a DNA-binding recognition helix. The recognition helix has a highly conserved 8-amino acid region specific to many homeobox genes. This suggested that DNA probes based on the conserved region of the third helix would serve as powerful tools to screen for homeobox genes. Stadler et al. (1992) used this strategy to identify homeobox genes expressed in the developing human craniofacial region. Probing a cDNA library constructed from human embryonic craniofacial tissue, they identified a novel homeobox cDNA encoding a protein they designated H6. The deduced H6 protein shares only 57 to 65% amino acid identity with previously reported homeodomains.
By gene amplification, Schorderet et al. (2008) demonstrated that the HMX1 gene encodes a deduced 347-amino acid protein that contains a classic homeobox domain of all NKX5 members.
By in situ hybridization of mouse embryos at embryonic day 10.5, Munroe et al. (2009) found that Hmx1 was prominently expressed in developing eye, trigeminal ganglion, second branchial arch, and dorsal root ganglia. There was also labeling of the otic placode and along the first branchial arch.
Stadler et al. (1992) performed mapping by study of somatic cell hybrids containing specific deletions of human chromosome 4 using PCR methods, after initial assignment by hybridization of radiolabeled H6 DNA to Southern blots containing DNA derived from a mouse/human somatic cell hybrid containing only human chromosome 4. The initial assignment to 4p16.1 was confirmed by studies of linkage between a collection of markers on chromosome 4 and a 250-bp amplification product from H6 that demonstrated a single-strand conformation polymorphism (SSCP) when electrophoresed on a nondenaturing acrylamide gel. Although HOX7 (142983) also maps to 4p16.1, it is unlikely that HOX7 and H6 are members of a homeobox cluster because the linkage data placed H6 more than 10 cM proximal to HOX7 and there was no significant amino acid identity of H6 and HOX7 outside the homeodomain.
Wang et al. (1997) mapped the murine Hmx1 homeobox gene to the proximal region of mouse chromosome 5 by backcross matings.
Represa et al. (2000) reviewed the genetic patterning of embryonic inner ear development, particularly the involvement of the HMX and PAX2 (167409) genes.
Schorderet et al. (2008) observed HMX1 expression in the external ear, lens, and retina of the mouse as early as E13.5, with polarized expression in the retina. Similar polarized expression was observed in the eye of 5- to 6-week-old human embryos with signals observed in the temporal and posterior retina. Although no HMX1 labeling was seen in the pinna or auricle of 20-week-old human fetuses, an intense hybridization signal was detected in the perichondrium surrounding all the intrinsic cartilage of the developing pinna. The developing auricular mesenchymal cells, including those of the developing intrinsic auricular ligaments, contained significant levels of HMX1 transcripts. Expression studies in the zebrafish showed similar localization, to the nasodorsal region of the eye and the ventral region of the otic placode as early as 24 hours postfertilization.
In affected members of a consanguineous Swiss family with oculoauricular syndrome (OCACS; 612109), Schorderet et al. (2008) identified homozygosity for a 26-bp deletion in the HMX1 gene (142992.0001). The parents of the proband were heterozygous for the deletion, which was not found in more than 250 ethnically matched controls or more than 500 patients with various eye diseases.
By direct sequencing of the HMX1 gene in 2 male cousins from a consanguineous Asian family with oculoauricular syndrome, Gillespie et al. (2015) identified homozygosity for a missense mutation (Q217P; 142992.0002) at a highly conserved residue. The parents of 1 of the cousins were heterozygous for the mutation, but DNA from the other set of parents was not available.
Schorderet et al. (2008) examined the effect of morpholino-based knockdown of Hmx1 in zebrafish and observed microphthalmia in all of the injected embryos and delayed or absent stratification of the retina in 73% and 27% of the embryos, respectively. Body length was not affected, and the phenotype could be rescued by coinjection of Hmx1 mRNA.
The mouse Dumbo (dmbo) mutation, which results in laterally-protruding ears, was recovered in a forward genetic mutagenesis screen. Munroe et al. (2009) found that dmbo/dmbo mice were smaller than their heterozygous littermates and that they suffered 40% perinatal mortality. The only major change in cranial bone morphology of dmbo/dmbo mice was displaced ear pinnae, which did not appear to affect hearing. Dmbo/dmbo mice also showed microphthalmia, but their eyes were otherwise clinically normal. Positional cloning and sequence analysis identified the dmbo mutation as a C-to-T transition in the coding region of Hmx1 that introduced an amber stop codon. Munroe et al. (2009) also found that a spontaneous mouse mutant called 'misplaced ears' (mpe) was due to an 8-bp deletion in the homeobox-coding exon of Hmx1.
In 3 affected members of a consanguineous Swiss family with oculoauricular syndrome (OCACS; 612109), Schorderet et al. (2008) identified homozygosity for a 26-bp deletion (215-240 del) in the HMX1 gene, predicted to cause a stop codon at position 112 and abolish the homeobox. The parents of the proband were heterozygous for the deletion, which was not found in more than 250 ethnically matched controls or more than 500 patients with various eye diseases.
By direct sequencing of the HMX1 gene in 2 male cousins from a consanguineous Asian family with oculoauricular syndrome (OCACS; 612109), Gillespie et al. (2015) identified homozygosity for a c.650A-C transversion (c.650A-C, NM_018942), resulting in a gln217-to-pro (Q217P) substitution at a highly conserved residue within the first helix of the encoded homeodomain. The parents of 1 of the cousins were heterozygous for the mutation, but DNA from the other set of parents was not available. In vitro studies demonstrated that the mutation has no effect on protein expression but adversely alters its function.
Gillespie, R. L., Urquhart, J., Lovell, S. C., Biswas, S., Parry, N. R. A., Schorderet, D. F., Lloyd, I. C., Clayton-Smith, J., Black, G. C. Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy. Invest. Ophthal. Vis. Sci. 56: 883-891, 2015. [PubMed: 25574057] [Full Text: https://doi.org/10.1167/iovs.14-15861]
Munroe, R. J., Prabhu, V., Acland, G. M., Johnson, K. R., Harris, B. S., O'Brien, T. P., Welsh, I. C., Noden, D. M., Schimenti, J. C. Mouse H6 homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass. BMC Dev. Biol. 9: 27, 2009. Note: Electronic Article. [PubMed: 19379485] [Full Text: https://doi.org/10.1186/1471-213X-9-27]
Represa, J., Frenz, D. A., Van de Water, T. R. Genetic patterning of embryonic inner ear development. Acta Otolaryng. 120: 5-10, 2000. [PubMed: 10779178] [Full Text: https://doi.org/10.1080/000164800760370756]
Schorderet, D. F., Nichini, O., Boisset, G., Polok, B., Tiab, L., Mayeur, H., Raji, B., de la Houssaye, G., Abitbol, M. M., Munier, F. L. Mutation in the human homeobox gene NKX5-3 causes an oculo-auricular syndrome. Am. J. Hum. Genet. 82: 1178-1184, 2008. [PubMed: 18423520] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.007]
Stadler, H. S., Padanilam, B. J., Buetow, K., Murray, J. C., Solursh, M. Identification and genetic mapping of a homeobox gene to the 4p16.1 region of human chromosome 4. Proc. Nat. Acad. Sci. 89: 11579-11583, 1992. [PubMed: 1360670] [Full Text: https://doi.org/10.1073/pnas.89.23.11579]
Wang, W., Yoshiura, K., Murray, J., Lufkin, T. Assignment of the murine Hmx1 homeobox gene to the proximal region of mouse chromosome 5. Mammalian Genome 8: 869-876, 1997. [PubMed: 9337406] [Full Text: https://doi.org/10.1007/s003359900598]