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

Isolated strabismus affects 1-5% of the general population(1). Most forms o f strabismus are multifactorial in origin; although there is probably an in herited component, the genetics of these disorders remain unclear. The cong enital fibrosis syndromes (CFS) represent a subset of monogenic isolated st rabismic disorders that are characterized by restrictive ophthalmoplegia, a nd 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 hav e been identified. Here, we report three mutations in ARIX (also known as P HOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription f actor protein previously shown to be required for nIIInIV development in mo use and zebrafish(1,12). Two of the mutations are predicted to disrupt spli cing, whereas the third alters an amino acid within the conserved brachyury -like domain(13,14). These findings confirm the hypothesis that CFEOM2 resu lts from the abnormal development of nIII/nIV (ref. 7) and emphasize a crit ical role for ARIX in the development of these midbrain motor nuclei(13-19) .