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Curr Opin Neurol. 2011 Dec 19;
Authors: Bonnet C, El-Amraoui A
Abstract
PURPOSE OF REVIEW: Usher syndrome (USH) is the most prevalent cause of hereditary deafness-blindness in humans. In this review, we pinpoint new insights regarding the molecular mechanisms defective in this syndrome, its molecular diagnosis and prospective therapies. RECENT FINDINGS: Animal models wherein USH proteins were targeted at different maturation stages of the auditory hair cells have been engineered, shedding new light on the development and
functioning of the hair bundle, the sound receptive structure. Improved protocols and guidelines for early molecular diagnosis of USH (USH genotyping microarrays, otochips and complete Sanger sequencing of the 366 coding exons of identified USH genes) have been developed. Approaches to alleviate or cure hearing and visual impairments have been initiated, leading to various degrees of functional rescuing. SUMMARY: Whereas the mechanisms underlying hearing impairment in USH patients are being unraveled, showing in particular that USH1 proteins are involved in the shaping of the hair bundle and the functioning of the mechanoelectrical transduction machinery, the mechanisms underlying the retinal defects are still unclear. Efforts to improve clinical diagnosis have been successful. Yet, despite some encouraging results, further development of therapeutic approaches is necessary to ultimately treat this dual sensory defect.
PMID: 22185901 [PubMed - as supplied by publisher]
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Several key problems still need to be addressed. For instance, it would be of great benefit to determine the structure of several PDE holoenzymes to fully understand their mechanisms of regulation. Therefore, substantial effort is being expended in this area. A concept gaining great support is the idea that different PDEs subserve different pools of cAMP and cGMP in the cell. We are only just beginning to be able to measure PDE activity in subcellular compartments of the cell in real time. This is an area that clearly needs to be developed, including identification of molecular mechanisms that provide and control PDE subcellular localization. We also need to identify good animal models that accurately reflect the regulation and roles of PDEs in human tissues as many examples now are available for different modes of regulation between mice and men. At a minimum, putative regulatory schemes identified from studies in mouse, Drosophila, or zebrafish need to be tested quickly in human tissues.
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Footnotes ?1 Abbreviations: PDE, phosphodiesterase; cAMP, adenosine 3?5?-cyclic monophosphate; cGMP, guanosine 3?5?-cyclic monophosphate; GAF, cyclic GMP, adenylyl cyclase, FhlA; CaM, calmodulin; PK, protein kinase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; CNS, central nervous system; ANP, atrial natriuretic peptide; NO, nitric oxide; PDP, 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one; BAY 60-7750, 2-(3,4-dimethoxybenzyl)-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methylimidazo[5,1-f] [1,2,4]triazin-4(3H)-one; PI3K, phosphatidylinositol 3-kinase; IGF1, insulin-like growth factor 1; OPC-33450, 6-[3-[3-cyclooctyl-3-[(1R*,2R*)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone; UCR, upstream conserved region; CRE, cAMP-responsive element-binding protein; RACK, receptor for activated C-kinase 1; AKAP, A-kinase anchoring proteins; ERK, extracellular signal-regulated kinase; BRL 50481, 3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene; PAS, Period, Arnt, and Sim; IBMX, 3-isobutyl-1-methylxanthine; BAY 73-6691, 1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one.
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If all of this sounds familiar, it should. It's reminiscent of the marketing tactics of cigarette manufacturers, who attempted for many years to sell cigarettes to younger people through youth-targeted advertising and lax enforcement of cigarette sales laws. This was an effort, of course, to hook younger children on cigarettes so that they would become lifetime smokers. The tobacco industry, of course, denies all of this, as would Pfizer if questioned about it. But, I think the pattern is quite similar -- and very much present today in the pharmaceutical industry.
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