Learn about PHOX2A
In 2001, we identified PHOX2A as the gene mutated in CFEOM2.
PHOX2A is a homeodomain transcription factor protein has a primary role in the generation and survival of adrenergic neurons and a population of brainstem motor neurons, as well as in the determination of the noradrenergic neurotransmitter phenotype. In mice, Phox2a and its paralog Phox2b are co-expressed in the developing locus coeruleus, in parasympathetic, cranial sensory, sympathetic and enteric ganglia, in hindbrain branchiomotor and visceral motor neurons, and in midbrain nIII and nIV somatic motor nerons. Morin et al (1997) demonstrated that Phox2a -/- mice lack the oculomotor and trochlear nuclei, the locus coeruleus, parasympathetic ganglia in the head, and the superior cervical ganglion. In addition, cranial sensory ganglia that normally express Phox2a are severely affected.
Of these structures, only nIII/nIV are absent in Phox2a-/- mice but present in Phox2b-/-, indicating that nIII/nIV are the only Phox2a-dependent neurons that do not also require Phox2b for normal development.
The absence of nIII/nIV in the Phox2a-/- mice corresponds to the predicted neuropathology of CFEOM2, as the absence of these nuceli would account for the bilateral ptosis and restrictive exotropia in these affected individuals. We predict that CFEOM2 results from aberrant development of these motor nuclei [Nakano et al 2001].
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *602753). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet. 2001 Nov;29(3):315-20.
Morin X, Cremer H, Hirsch MR, Kapur RP, Goridis C, Brunet JF. Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron. 1997 Mar;18(3):411-23.
Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development. 1997 Oct;124(20):4065-75
Guo S, Brush J, Teraoka H, Goddard A, Wilson SW, Mullins MC, Rosenthal A.. Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a. Neuron. 1999 Nov;24(3):555-66.