HOXA1 Gene

The HoxA1 gene is located on the P arm of chromosome 7 and encodes for homeoboxA trascription factors. HomeoboxA TF's are thought to be responsible for cell differentation and gene expression for embryotic development of components of the ear, vascular structure of the neck and the hind brain in humans. [1][2] HoxA1 is expressed early in embryonic development and is essential to proper development of the head and brain [3].

Figure 2. HOXA1 protein structure [6

] 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 durring segmenting of the embyonic hindbrain into seven transient compartments called rhombomers. Each rhombomer has a distinct set of cellular and molecular properties that 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 [[http:// 9]].
HoxA1 regulation cascade

HoxA1 regulation cascade. [9]

HoxA1 is the only anterior Hox gene linked to a human syndrome. The HoxA1 gene is a highly conserved gene. Alignment of this gene between humans (1), the common house mouse (2), the chimpanze (3) and cattle (4) showed the most commonality in nucleotide sequence between humans and chimpanzes. The humans, chimp and house mouse transcribe this gene from the bottom strand of DNA where as the gene is transcribed from 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

Alignment from Geneious (1) Human (2) House Mouse (3) Chimpanze (4) Cattle

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 chimpanze sequence. The chimpanze and human sequence are very close on the tree diagram indicating that species divergence has been a more recent occurance compared to the house mouse and cattle. 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 disord
Duane syndrome

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

]er. 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 malformations, cerebrovascular anomalies, and cognitive function [7]. ABDS was studied in those of Athabascan indian heritage 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]. 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].

One of the inborn phenotypes is the result of SNP-based linkage to a 175-176 guanine insertion, resulting in a fram shift mutation that intorduces 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 mutatnt variation lacks these DNA binding domains which most often renders the protein TF inactive or highly ineffective [3].

Over expression of HoxA1 is prevelent in oral squamous cell carcinomas when compated to healthy mucosal cells. The HoxA1 gene is not only responsible for cell differentation 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].

  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.
  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.