The HoxA1 gene is located on the P arm of chromosome 7 and encodes for homeoboxA transcription factors. HomeoboxA TF's are thought to be responsible for cell differentiation and gene expression for embryon
HOXA1 Chromosome location

HoxA1 Gene location. On short arm of chromosome 7. (10)

ic development of components of the ear, vascular structure of the neck and the hind brain in humans [1][2]. The HOX genes were discovered in fruit flies by German geneticists Christiane Nüsslein-Volhard and Eric F. Wieschaus in the early 1980's and were awarded a Nobel Prize in 1995 for their work. The homeobox proteins expressed by the Hox genes get their name from the word homeotic, meaning "something that has been changed to the likeness of something else" [10].

Structure and ActivityEdit

The HoxA1 gene is composed of two exons and codes for a 60 amino acid homeodomain with a helix-turn-helix motif (Figure 2) DNA binding domain that allows HoxA1 TF's to activate, repress or enhance gene expression during segmenting of the embryonic hindbrain into seven transient compartments called rhombomers. Each rhombomer has a distinct set of cellular and molecular properties that

Figure 2. HOXA1 protein structure, helix-turn-helix motif (6).

are necessary for organizing groups of immature neurons into functional networks that will eventually mediate important functions such as breathing, eye movement, hearing and chewing [3]. Of the 39 Hox genes, HoxA1 is the first to be expressed and starts the regulation cascade of gene expression during embryonic development of the following genes; Foxd3, Lhx5, Hnf1b, Zic1, Pax8 and Fgfr3, all of which are responsible for rhombomer development [9]. HoxA1 is the only anterior Hox gene linked to a human syndrome.
HoxA1 regulation cascade

HoxA1 regulation cascade. HoxA1, in the middle of the diagram is shown to regulate genes in green and red. Arrows diverging from these genes show the anatomical areas that they regulate during embryonic development. (9)

Gene Alignment with Other SpeciesEdit

The HoxA1 gene is a highly conserved gene. Alignment of this gene between humans (1), the common house mouse (2), the chimpanzee (3) and cattle (4) showed the most commonality in nucleotide sequence between humans and chimpanzees. The humans, chimp and house mouse transcribe this gene from the bottom strand of DNA where as the gene is transcribed fro

Notice the commong intron location between 1,2 &3. (1) Human (2) House Mouse (3) Chimpanze (4) Cattle. Alignment, complements of Geneious software.

m the top strand in cattle. Alignment between humans, chimps and the house mouse show a similarly sized intron length between the 1st and 2nd exons. The tree diagram of these 4 species show that cattle has the largest divergence from the 4 species and that the mouse is significantly closer to the human and chimpanzee sequence. The chimpanzee and human sequence are very close on the tree diagram indicating that species divergence has been a more recent occurrence compared to the house mouse and cattle. (Alignment generated using Geneious software).

Phenotypes Associated with SNPsEdit

There are several inborn phenotypes for mutations of HoxA1, including; Duane syndrome type III, Bosley-Salih-Alorainy syndrome (BSAS), Athabascan brainstem dysgenesis syndrome (ABDS), mental retardation and autism spectrum disorder. Duane syndrome is a congenital disease that effects the abduction of the eyes outward [5]. BSAS has been studied in the Saudi Arabian population and is characterized by Duane Syndrome, inner ear
Duane syndrome

Duane Syndrome in the left eye. The right eye looks outward but the left eye remains looking up. (5)

malformations, cerebrovascular anomalies, and impared cognitive function [7]. ABDS was studied in those of Athabascan indian heritage of Navajo and Apache descent and is characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies [8].

The inborn phenotypes are the result of SNP-based linkage to a 175-176 guanine insertion, resulting in a frame shift mutation that introduces a premature stop codon in exon 1. The wild type HoxA1 gene contains a PBX binding motif on Exon 1 and a Homeodomain on Exon 2. Both of these areas are essential for the TF's ability to bind DNA. The mutant variation lacks these DNA binding domains which most often render the TF inactive or highly ineffective [3].

HoxA1 and CancerEdit

Mutations in HoxA1 have also been linked to a range of squamous cell carcinomas (specifically in the head and neck) and breast cancer, typically over expression of HoxA1 is linked with a poor disease prognosis [4].

Over expression of HoxA1 is prevalent in oral squamous cell carcinomas when compared to healthy mucosal cells. The HoxA1 gene is not only responsible for cell differentiation and rhombomer organization, but also cell proliferation and when over expressed has oncogenic properties associated with tumor differentiation and proliferative potential that is predictive of poor survival rates [4].


  1. Wikipedia. Homeobox-A1 page. Last modified 12/29/2010.
  2. Boston Childrens Hospital. Learn about HoxA1 related syndromes. Engle Laboratory. Last modified 12/15/2003.
  3. Boston Childrens Hospital. Learn about HoxA1. Engle Laboratory. Last modified UNK.
  4. Bitu CC, etal. HOXA1 is over expressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis. BMC Cancer. 2012 Apr 12;12:146.
  5. Wkipedia. Duane Syndrome. Last modified 9/15/2012.
  6. UCSC Genome Bioinformatics. Human Genome HoxA1 (S79868) Description Page. Last modified UNK.
  7. Bosley TM, et al. Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology. 2007 Sep 18;69(12):1245-53.
  8. Holve et al. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A. 2003 Jul 15;120A(2):169-73.
  9. Nadja Makki, Mario R. Capecchi. Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development. Developmental Biology. Volume 357, Issue 2, 15 September 2011, Pages 295–304.
  10. Genetic Home Reference. HOXA1. last modified 9/18/2012.
  11. Wikipedia. Hox Gene. Last modified 8/24/2012.