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Query: UMLS:C0038379 (strabismus)
 9,317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systematic genetic screens in zebrafish have led to the discovery of mutations that affect organizer function and development. The molecular isolation and phenotypic analysis of the affected genes have revealed that TGF-beta signals of the Nodal family play a key role in organizer formation. The activity of the Nodal signals Cyclops and Squint is regulated extracellularly by the EGF-CFC cofactor One-eyed Pinhead and by antagonists belonging to the Lefty family of TGF-beta molecules. In the absence of Nodal signaling, the fate of cells in the organizer is transformed from dorsal mesoderm to neural ectoderm. Differential Nodal signaling also patterns the organizer along the anterior-posterior axis, with high levels required for anterior cell fates and lower levels for posterior fates. In addition, Nodal signaling cooperates with the homeodomain transcription factor Bozozok in organizer formation and neural patterning. The combination of genetic, molecular and embryological approaches in zebrafish has thus provided a framework to understand the mechanisms underlying organizer development.
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PMID:Nodal signaling and the zebrafish organizer. 1129 59

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.
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PMID:Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. 1160 Aug 83

The congenital fibrosis syndromes (CFS), including congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DS), are rare congenital strabismus syndromes that present with nonprogressive restrictive ophthalmoplegia with or without ptosis. Although historically believed to result from primary extraocular muscle (EOM) fibrosis, our laboratory's work is based on the hypothesis that these disorders result from distinct, but analogous, developmental defects of the oculomotor (nIII), trochlear (nIV), and abducens (nVI) nuclei. We have defined three inherited CFEOM phenotypes (CFEOM1-3) and have mapped each phenotype to a distinct genetic locus (FEOM1-3). Individuals with CFEOM1 are born with bilateral ptosis and both eyes fixed in a downward position with absent upgaze and aberrant horizontal gaze. This disorder maps to the FEOM1 locus on chromosome 12cen.(1,2) Neuropathology studies of CFEOM1 reveal the absence of the superior division of oculomotor nerve and its corresponding alpha motor neurons in the midbrain, with abnormalities of target EOMs.(3) These neuropathology findings parallel those previously identified in Duane syndrome, in which there is an absence of nVI and the abducens nerve.(4,5) Individuals with CFEOM2 are born with bilateral ptosis and exotropia. This atypical form of CFEOM maps to the FEOM2 locus on chromosome 11q13 and results from mutations in ARIX (PHOX2A).(6,7) ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish.(8,9) Together, these findings support the hypothesis that the congenital fibrosis syndromes result from parallel defects in nIII, nIV, and nVI nuclear development. Functional studies of the CFEOM genes should provide additional insight into the unique features of the extraocular lower motor neuron axis in health and disease. (For full (refs. 1-9), see reference list of the main paper.)
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PMID:Applications of molecular genetics to the understanding of congenital ocular motility disorders. 1196 Jul 93

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a complex strabismus syndrome that results from mutations in the homeodomain transcription factor PHOX2A. To define the clinical and neuroimaging features of patients with this autosomal recessive syndrome, we studied 15 patients with genetically defined CFEOM2. All patients underwent full neurological, neuro-ophthalmological and orthoptic assessments. Twelve patients had pupillary pharmacological testing and nine had 3.0 tesla MRI of the brain, brainstem and orbits. Patients were born with severe bilateral ptosis and exotropia with almost complete bilateral absence of adduction, elevation, depression and intorsion. Variable abduction was present prior to strabismus surgery in 14 patients, and central ocular motility reflexes (smooth pursuit, saccades, vestibulo-ocular reflex and optokinetic reflex) were intact except for convergence. Pupillary light and near reflexes were not present, but irises were anatomically normal and responded to pupillary pharmacology. Neuroimaging of brain and brainstem was remarkable for the anatomical absence of cranial nerve (CN) 3 and probably CN 4 bilaterally. Therefore, the CFEOM2 phenotype and neuroimaging are both consistent with the congenital absence of CNs 3 and 4. Additional features included presence of most central ocular motility reflexes, a central lack of pupillary responsiveness of uncertain aetiology and modest phenotypic variability that does not correlate with specific PHOX2A mutations. Clinical presentation, neuroimaging and Phox2a-/- animal models all support the concept that CFEOM2 is a primary neurogenic abnormality with secondary myopathic changes.
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PMID:Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A. 1681 72