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

Abstract

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 nuclei3,4,5. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2)6,7,8,9,10, 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 development in mouse and zebrafish11,12. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain13,14. 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 nuclei13,14,15,16,17,18,19.

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Figure 1: Haplotype analysis of Turkish CFEOM2 pedigree CQ.
Figure 2: Physical map of the FEOM2 critical region (boxed in gray).
Figure 3: Mutation analysis of ARIX by direct automated sequencing and by DHPLC screening on the WAVE.
Figure 4: Absent CQ ARIX exon 1 to 2 transcript resulting from the exon 1 donor splice site mutation.
Figure 5: ARIX amino-acid sequence and alignment with orthologous and paralogous sequences.
Figure 6: Schematic lateral view of the brainstem and left orbit in an individual with CFEOM2, showing the proposed neuropathology.

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Acknowledgements

We thank the affected families for their participation in this study, W.-M. Chan, C. St. Hilaire and D. Southwell for technical assistance, C. Walsh for a subset of control DNA samples and J. Scharf for his critical review of the manuscript. This work was supported by National Eye Institute EY12498 and by the Children's Hospital Mental Retardation Research Center (P30 HD18655).

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Correspondence to Elizabeth C. Engle.

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Nakano, M., Yamada, K., Fain, J. et al. Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 29, 315–320 (2001). https://doi.org/10.1038/ng744

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