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

Nat Genet. 2001 Nov;29(3):315-20. doi: 10.1038/ng744.


Isolated strabismus affects 1-5% of the general population. 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). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), 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 development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Contig Mapping
  • DNA Mutational Analysis
  • Duane Retraction Syndrome / genetics*
  • Eye Abnormalities / genetics
  • Female
  • Haplotypes / genetics
  • Homeodomain Proteins / genetics*
  • Homozygote*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nerve Tissue Proteins
  • Pedigree
  • Phenotype
  • Polymorphism, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • Strabismus / genetics*
  • Transcription Factors / genetics*


  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • PHOX2A protein, human
  • Phox2a protein, mouse
  • RNA, Messenger
  • Transcription Factors

Associated data

  • GENBANK/AP000593
  • GENBANK/AP000812
  • GENBANK/O14813
  • RefSeq/NM_005169