Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2

Isolated strabismus affects 1-5% of the general population¹. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS)². Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei^3-5. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2)^6-10, but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for NIII/NIV NIII/NIV development in mouse and zebrafish^11,12. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain^13,14. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of NIII/NIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei^13-19.