Alternative titles; symbols
HGNC Approved Gene Symbol: HOXA1
SNOMEDCT: 720518006, 720567008;
Cytogenetic location: 7p15.2 Genomic coordinates (GRCh38) : 7:27,092,993-27,096,000 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p15.2 | Athabaskan brainstem dysgenesis syndrome | 601536 | Autosomal recessive | 3 |
| Bosley-Salih-Alorainy syndrome | 601536 | Autosomal recessive | 3 |
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on 4 separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. Hong et al. (1995) determined the structure of the first gene in the homeobox A cluster, HOXA1, by cloning its full-length cDNA, which predicts a protein of 335 amino acids. In vitro translation produced the expected 36-kD protein. An alternatively spliced cDNA was also obtained. In PA-1 teratocarcinoma cells, HOXA1 was induced by retinoic acid earlier than other HOXA cluster genes.
HOX genes are required during the morphogenesis of both vertebrate digits and external genitals. Lonfat et al. (2014) investigated whether transcription in such distinct contexts involves a shared enhancer-containing landscape. They showed that the same regulatory topology is used, albeit with some tissue-specific enhancer-promoter interactions, which suggested the hijacking of a regulatory backbone from one context to another. In addition, comparable organizations were observed at both HOXA1 and HOXD1 (142987) clusters, which separated through genome duplication in an ancestral invertebrate animal. Lonfat et al. (2014) proposed that this convergent regulatory evolution was triggered by the preexistence of some chromatin architecture, thus facilitating the subsequent recruitment of the appropriate transcription factors. Lonfat et al. (2014) argued that regulatory topologies may have both favored and constrained the evolution of pleiotropic developmental loci in vertebrates.
Xiong et al. (2020) found that Bap1 (603089) facilitated expression of Hoxa1, which was required for self-renewal of mouse hematopoietic stem cells (HSCs). Ttll5 (612268) and Ttll7 (618813) glutamylated Bap1 at glu651 in HSCs, whereas Ccp3 (617346) removed Bap1 glutamylation. Bap1 glutamylation promoted its interaction with Ube2o (617649) and accelerated lys48-linked ubiquitination of Bap1 for its degradation. Degradation of Bap1 suppressed Hoxa1 expression, thereby enhancing HSC self-renewal and hematopoiesis.
Apiou et al. (1996) used fluorescence in situ hybridization to localize the HOXA gene cluster precisely to 7p15.3.
Autism Spectrum Disorder Susceptibility
Ingram et al. (2000) identified a common polymorphism in the HOXA1 gene: an A-to-G substitution at codon 218, changing the codon for one histidine in a series of histidine repeats to an arginine at position 73. The frequency of the G allele was 20 to 60% among the Coriell Human Diversity Panel, but was not identified in any individuals of Asian origin including Indians, Japanese, and Chinese. The frequency of the G allele was 0.202 in 57 probands with autism spectrum disorders and 0.203 in their 32 affected relatives. The frequency of the G allele in 134 unaffected relatives of subjects with an Asperger spectrum disorder was 0.164. The frequency of the G allele in the convenience population for this study was 0.109. In the autism spectrum disorder families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions. Among affected offspring, a significant deviation from mendelian expectation in gene transmission was observed. Ingram et al. (2000) suggested that there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to autism spectrum disorders.
Bosley-Salih-Alorainy/Athabaskan Brainstem Dysgenesis Syndromes
Tischfield et al. (2005) carried out SNP-based linkage analysis in a Saudi Arabian family with Bosley-Salih-Alorainy syndrome (BSAS; 601536) and identified a single, fully informative 8.5-Mb region on 7p15.3-p14.3 in which only the affected children were homozygous. Further analysis narrowed the linkage to a region of homozygosity of approximately 300 kb on 7p15.2. Because of similarities between the BSAS phenotype and the pathology of the Hoxa1 -/- mouse, and because the HOXA cluster falls in the haploidentical region, Tischfield et al. (2005) analyzed the HOXA1 gene in Saudi Arabian individuals with BSAS and found a homozygous guanine insertion, 175_176insG, predicted to result in a reading frameshift and the introduction of a premature stop codon (142955.0001). A Turkish individual with BSAS had a homozygous 84C-G transversion resulting in the substitution of a stop codon for a tyrosine residue (Y28X; 142955.0002). Noting the phenotypic overlap of BSAS, the Hoxa1 knockout mouse, and Athabaskan brainstem dysgenesis syndrome, Tischfield et al. (2005) analyzed genomic DNA from 5 of the reported individuals with ABDS and 4 of their phenotypically normal parents. All 5 affected individuals were homozygous across the HOXA1 locus and carried a homozygous 76C-T HOXA1 mutation resulting in substitution of a stop codon for arginine (R26X; 142955.0003). Tischfield et al. (2005) pointed out that to their knowledge this was the first report of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.
Because 1 of the patients of Tischfield et al. (2005) with a mutation in HOXA1 had Duane anomaly and asymptomatic left carotid hypoplasia (see 142955.0001), Tischfield et al. (2006) analyzed the HOXA1 gene in 101 probands with isolated Duane anomaly (DA) and 30 with DA and other symptoms. None in this group harbored a mutation in SALL4 (607343) or ROBO3 (608630), and none were members of a pedigree whose phenotype maps to the DURS2 (604356) locus. No mutation was detected in any proband; the authors concluded that HOXA1 mutations are a rare cause of isolated Duane anomaly.
Lufkin et al. (1991) generated mice deficient in Hoxa1 by homologous recombination. Heterozygous mice were normal but homozygous mice died at birth from anoxia and had numerous defects that were centered at the levels of rhombomeres 4 to 7 and included delayed hindbrain neural tube closure, absence of certain cranial nerves and ganglia, and malformed inner ears and bones of the skull. Mark et al. (1993) further characterized the anatomic defects in Hoxa1 -/- mutant mice. Three-dimensional reconstructions of Hoxa1 -/- rhombencephalon revealed that it bears only 5 rhombomeric structures instead of the normal 7. The first 3 of these rhombomeres appeared normal as judged from the distribution pattern of Crabp1 (180230) transcripts in the neuroectoderm and from histologic analysis of the cranial nerve components derived from these structures. In contrast, the neural crest cell-free region normally located opposite rhombomere-5 is absent in Hoxa1 -/- embryos, and motor neurons of the facial and abducens nerves, which normally differentiate within rhombomeres 4, 5, and 6, are missing in Hoxa1 -/- fetuses. These data suggested that rhombomere 4 is markedly reduced, whereas rhombomere 5 is almost absent, in Hoxa1 -/- embryos. Remnants of rhombomeres 4 and 5 appeared to be fused caudally with rhombomere 6 to form a single fourth rhombomeric structure. Mark et al. (1993) found that the mutual relationship along the rostrocaudal axis between the otic pit and the neuroepithelial site of int2 protein secretion was not significantly changed in Hoxa1 -/- embryos. However, the abnormal relationship between the rhombencephalon and the epithelial inner ear may account for the aplasia and faulty differentiation of the membranous labyrinth, the disruption of the cartilaginous otic capsule, and the disorganization of some middle ear structures.
Pasqualetti et al. (2001) demonstrated that a single maternal administration of a low dose of the vitamin A metabolite retinoic acid was sufficient to compensate the requirement for Hoxa1 function in Hoxa1-deficient mice. A single dose of retinoic acid rescued cochlear and vestibular defects in mutant fetuses without affecting the development of wildtype fetuses. These results identified a temporal window of susceptibility to retinoids that is critical for mammalian inner ear specification, and provided the first evidence that a subteratogenic dose of vitamin A derivative can be effective in rescuing a congenital defect in the mammalian embryo.
Kmita et al. (2005) described mice that were lacking all Hoxa and Hoxd functions in their forelimbs. They showed that such limbs are arrested early in their developmental patterning and display severe truncations of distal elements, partly owing to the absence of Sonic hedgehog (600725) expression. These results indicated that the evolutionary recruitment of Hox gene function into growing appendages might have been crucial in implementing hedgehog signaling, subsequently leading to the distal extension of tetrapod appendages. Accordingly, Kmita et al. (2005) suggested these mutant limbs may be reminiscent of an ancestral trunk extension, related to that proposed for arthropods.
Makki and Capecchi (2012) found that deletion of Hoxa1 in mice caused a variety of malformations of the cardiac outflow tract and great arteries in late-stage embryos. Defects showed variable penetrance and included interrupted aortic arch type B, aberrant subclavian artery, and tetralogy of Fallot (see 187500). During early mouse embryogenesis, Hoxa1 was expressed in precursors of cardiac neural crest cells, and it directed expression of genes important for neural crest specification.
In affected members of 3 consanguineous Saudi Arabian families with Bosley-Salih-Alorainy syndrome and in a 4-year-old Saudi Arabian boy, born of consanguineous parents, with Duane anomaly and hypoplastic left carotid artery (BSAS; see 601536), Tischfield et al. (2005) identified homozygosity for a guanine insertion, 175_176insG. The mutation segregated with the disorder in the families; haplotype analysis indicated a founder effect. The mutation was predicted to result in a frameshift and premature termination, although functional studies of the variant and studies of patient cells were not performed.
Bosley et al. (2008) identified the 175_176insG mutation in affected members of 2 additional consanguineous Saudi Arabian families with BSAS. The mutation was predicted to result in a truncated protein and absence of HOXA1 activity. Five patients had conotruncal or septal heart defects.
In an individual with Bosley-Salih-Alorainy syndrome (BSAS; see 601536) from a Turkish family, Tischfield et al. (2005) found homozygosity for an 84C-G transversion resulting in substitution of a stop codon for a tyrosine residue (Y28X). Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In individuals with Athabaskan brainstem dysgenesis syndrome (ABDS; 601536), reported in Native American tribes, Tischfield et al. (2005) found homozygosity for a 76C-T transition in the HOXA1 gene, predicted to result in the substitution of a stop codon for an arginine residue (arg26 to ter; R26X). The mutation was heterozygous in the parents and absent from 344 control chromosomes; haplotype analysis was consistent with a founder effect. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
Bosley et al. (2008) identified the R26X mutation in 3 patients from 3 families of Native American origin with ABDS. All had deafness, horizontal gaze palsy, and developmental delay, and 2 had congenital cardiac defects.
In a Saudi Arabian patient, born of consanguineous parents, with Bosley-Salih-Alorainy syndrome (BSAS; 601536), Bosley et al. (2008) identified a homozygous 1-bp deletion (185delG) in the HOXA1 gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. The patient had Duane retraction anomaly, horizontal gaze restriction, and deafness, but normal cognition.
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Ingram, J. L., Stodgell, C. J., Hyman, S. L., Figlewicz, D. A., Weitkamp, L. R., Rodier, P. M. Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 62: 393-405, 2000. [PubMed: 11091361] [Full Text: https://doi.org/10.1002/1096-9926(200012)62:6<393::AID-TERA6>3.0.CO;2-V]
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Pasqualetti, M., Neun, R., Davenne, M., Rijli, F. M. Retinoic acid rescues inner ear defects in Hoxa1 deficient mice. Nature Genet. 29: 34-39, 2001. [PubMed: 11528388] [Full Text: https://doi.org/10.1038/ng702]
Tischfield, M. A., Bosley, T. M., Salih, M. A. M., Alorainy, I. A., Sener, E. C., Nester, M. J., Oystreck, D. T., Chan, W.-M., Andrews, C., Erickson, R. P., Engle, E. C. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nature Genet. 37: 1035-1037, 2005. [PubMed: 16155570] [Full Text: https://doi.org/10.1038/ng1636]
Tischfield, M. A., Chan, W.-M., Grunert, J.-F., Andrews, C., Engle, E. C. HOXA1 mutations are not a common cause of Duane anomaly. Am. J. Med. Genet. 140A: 900-902, 2006. [PubMed: 16528738] [Full Text: https://doi.org/10.1002/ajmg.a.31167]
Xiong, Z., Xia, P., Zhu, X., Geng, J., Wang, S., Ye, B., Qin, X., Qu, Y., He, L., Fan, D., Du, Y., Tian, Y., Fan, Z. Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis. J. Exp. Med. 217: e20190974, 2020. Note: Electronic Article. [PubMed: 31699823] [Full Text: https://doi.org/10.1084/jem.20190974]