Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A continuously growing body of evidence suggests that dysregulation of noradrenergic (NA) neurons is implicated in the etiology and pathophysiology of various human diseases such as depression, drug addiction, and autonomic dysfunction. An efficient NA neuron-specific promoter is potentially valuable to investigate the precise role of NA neurons in normal as well as in diseased brain and to treat the associated disorders by gene therapy. In this study, we tested a novel strategy to modify genetically the promoter of the human dopamine beta-hydroxylase (hDBH) gene to overcome its inherent weakness while maintaining its cell-type specificity. We optimized the nucleotide sequence motifs of PHOX2-binding sites (PRS2 and PRS3) residing within the hDBH promoter. Optimization of both PRS2 and PRS3 motifs significantly increased their binding affinities to PHOX2A, leading to a dramatic increase in the promoter strength (>20-fold). More importantly, these modifications do not alter the level of transgene expression in non-NA cells either in vitro or in vivo, demonstrating tight cell-type specificity. This work shows that a cellular gene promoter can be genetically modified to strengthen its promoter activity without losing cell-type specificity by optimizing critical cis-regulatory elements. Our genetically engineered promoter may be useful for cell-type-specific gene targeting as well as for generating in vivo animal models with altered gene expression in a specific cell type.
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PMID:Genetically engineered dopamine beta-hydroxylase gene promoters with better PHOX2-binding sites drive significantly enhanced transgene expression in a noradrenergic cell-specific manner. 1558 14

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