Alternative titles; symbols
HGNC Approved Gene Symbol: PHOX2A
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:72,239,077-72,244,176 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Fibrosis of extraocular muscles, congenital, 2 | 602078 | Autosomal recessive | 3 |
The PHOX2A gene encodes a homeodomain transcription factor that functions in midbrain motor neuron development (summary by Nakano et al., 2001).
To identify proteins that regulate transcription of the neurotransmitter biosynthetic gene dopamine beta-hydroxylase (DBH; 223360), Zellmer et al. (1995) screened a rat adrenal medulla expression library with the sequence of an enhancer from the rat DBH gene promoter region. They isolated a cDNA encoding a protein with a paired-like homeodomain. Since the homeodomain was most similar to that of the Drosophila 'aristaless' gene, the gene was designated Arix for 'aristaless homeobox homology.' The sequence of the predicted 281-amino acid protein is 97% identical to that of mouse Phox2. Northern blot and RNase protection analyses revealed that Arix is expressed only in noradrenergic, DBH-positive tissues. When expressed in rat cells, Arix regulated transcriptional activity from the DBH promoter and from the promoter of the tyrosine hydroxylase gene (TH; 191290), which encodes the initial enzyme of the catecholamine biosynthetic pathway. Zellmer et al. (1995) suggested that their results indicated that Arix may be involved in regulating the specificity of expression of the catecholamine biosynthetic genes.
Johnson et al. (1996) isolated ARIX clones from a human genomic library.
Using analysis of somatic cell hybrid panels and fluorescence in situ hybridization, Johnson et al. (1996) mapped the ARIX gene to 11q13.3-q13.4. By interspecific backcross analysis, the authors mapped the mouse Arix gene to chromosome 7, approximately 50 cM distal to the centromere, in a region showing conservation of synteny with human chromosome 11.
Merscher et al. (1997) showed that the PHOX2A gene maps to a region of 11q in which type 2 Meckel syndrome (MKS2; 603194) was found to map by Roume et al. (1998). Meckel syndrome is characterized by occipital meningoencephalocele with fibrocystic changes of the kidneys and liver and postaxial polydactyly. Roume et al. (1998) pointed out that not only do PHOX2A and MKS2 map to the same chromosomal region but also the Phox2a gene is strongly expressed in the mouse hindbrain (Pattyn et al., 1997).
In affected members of 4 pedigrees segregating congenital fibrosis of extraocular muscles type 2 (CFEOM2; 602078), Nakano et al. (2001) identified homozygous mutations in the ARIX gene (602753.0001-602753.0003).
Pattyn et al. (1997) reported that Phox2a and Phox2b are coexpressed at most sites, suggesting a broader role for Phox2 genes in the specification of autonomic nervous system and cranial motor nuclei than revealed by the Phox2a knockout mice. Morin et al. (1997) generated mice sufficient in Phox2a by targeted disruption. Phox2a -/- mice completed lacked a locus ceruleus, the main noradrenergic center of the brain. Furthermore, parasympathetic ganglia in the head are missing, and the superior cervical ganglion as well as cranial sensory ganglia that normally express Phox2a are severely affected.
The transient expression of dopamine beta-hydroxylase in neuroblasts is abolished in Phox2a -/- mice, providing evidence that Phox2a controls noradrenergic traits in vivo. Furthermore, the expression of the glial cell-derived neurotrophic factor (GDNF; 600837) receptor subunit RET (164761) is dramatically reduced, and there is a massive increase in apoptosis of ganglion cells, which are known to depend on GDNF in vivo. Therefore, Morin et al. (1997) concluded that Phox2a appears to regulate conventional differentiation traits and the ability of neurons to respond to essential survival factors.
In the proband of a consanguineous Turkish family (CQ) with congenital fibrosis of extraocular muscles-2 (CFEOM2; 602078), Nakano et al. (2001) identified homozygosity for a G-to-A transition at the +1 position of the GT splice donor site of exon 1 of the PHOX2A gene. RT-PCR of patient lymphoblast RNA showed that the mutation resulted in skipping of exons 1 and 2.
In the proband of a consanguineous Saudi Arabian family (Z) with congenital fibrosis of extraocular muscles-2 (CFEOM2; 602078), Nakano et al. (2001) identified homozygosity for a G-to-A transition at the -1 position of the AG splice acceptor site of exon 3 of the PHOX2A gene. The mutation was predicted to result in abnormal splicing.
In affected members of 2 consanguineous Saudi Arabian families (BB and BD) with congenital fibrosis of extraocular muscles-2 (CFEOM2; 602078), Nakano et al. (2001) identified a homozygous C-to-T mutation at nucleotide 386 (386C-T) in exon 1 of the PHOX2A gene, resulting in an alanine-to-valine substitution at codon 72 (A72V). This mutation occurred within the brachyury-like domain, a short peptide sequence (amino acids 61 to 75) of ARIX with high homology to 'brachyury' (601397) and PAX9 (167416). The first 152 amino acids of ARIX, encompassing both the brachyury-like and homeodomain segments, are 100% identical in human, mouse, and rat orthologs, and alanine-72 is conserved between ARIX and its paralog PMX2B (also known as PHOX2B; 603851). However, the mutation could also affect splicing since it occurs at position -3 of the exon 1 splice donor sequence.
Johnson, K. R., Smith, L., Johnson, D. K., Rhodes, J., Rinchik, E. M., Thayer, M., Lewis, E. J. Mapping of the ARIX homeodomain gene to mouse chromosome 7 and human chromosome 11q13. Genomics 33: 527-531, 1996. [PubMed: 8661014] [Full Text: https://doi.org/10.1006/geno.1996.0230]
Merscher, S., Bekri, S., de Leeuw, B., Pedeutour, F., Grosgeorge, J., Shows, T. B., Mullenbach, R., Le Paslier, D., Nowak, N. J., Gaudray, P. A 5.5-Mb high-resolution integrated map of distal 11q13. Genomics 39: 340-347, 1997. [PubMed: 9119371] [Full Text: https://doi.org/10.1006/geno.1996.4460]
Morin, X., Cremer, H., Hirsch, M.-R., Kapur, R. P., Goridis, C., Brunet, J.-F. Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron 18: 411-423, 1997. [PubMed: 9115735] [Full Text: https://doi.org/10.1016/s0896-6273(00)81242-8]
Nakano, M., Yamada, K., Fain, J., Sener, E. C., Selleck, C. J., Awad, A. H., Zwaan, J., Mullaney, P. B., Bosley, T. M., Engle, E. C. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nature Genet. 29: 315-320, 2001. [PubMed: 11600883] [Full Text: https://doi.org/10.1038/ng744]
Pattyn, A., Morin, X., Goridis, C., Brunet, J. F. Expression and interaction of the two closely related homeobox genes PHOX2a and PHOX2b during neurogenesis. Development 124: 4065-4075, 1997. [PubMed: 9374403] [Full Text: https://doi.org/10.1242/dev.124.20.4065]
Roume, J., Genin, E., Cormier-Daire, V., Ma, H. W., Mehaye, B., Attie, T., Razavi-Encha, F., Fallet-Bianco, C., Buenerd, A., Clerget-Darpoux, F., Munnich, A., Le Merrer, M. A gene for Meckel syndrome maps to chromosome 11q13. Am. J. Hum. Genet. 63: 1095-1101, 1998. [PubMed: 9758620] [Full Text: https://doi.org/10.1086/302062]
Zellmer, E., Zhang, Z., Greco, D., Rhodes, J., Cassel, S., Lewis, E. J. A homeodomain protein selectively expressed in noradrenergic tissue regulates transcription of neurotransmitter biosynthetic genes. J. Neurosci. 15: 8109-8120, 1995. [PubMed: 8613746] [Full Text: https://doi.org/10.1523/JNEUROSCI.15-12-08109.1995]