RESUMEN

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.

Asunto(s)

Síndrome de Retracción de Duane/genética , Proteínas de Homeodominio/genética , Homocigoto , Mutación/genética , Estrabismo/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Contig , Análisis Mutacional de ADN , Anomalías del Ojo/genética , Femenino , Haplotipos/genética , Humanos , Masculino , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso , Linaje , Fenotipo , Polimorfismo Genético/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia