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Investigating the DNA binding and transactivation activity of rdyCRX as a molecular basis for retinal dysplasia in Felis catus (943.1)
Ist Teil von
The FASEB journal, 2014-04, Vol.28 (S1), p.n/a
Ort / Verlag
The Federation of American Societies for Experimental Biology
Erscheinungsjahr
2014
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
In a pedigree developed from affected Abyssinian cats, an early onset rod‐cone dysplasia (Rdy) was identified and demonstrates an autosomal dominant inheritance. This is an excellent model for inherited retinal disorders such as retinitis pigmentosa (RP), cone‐rod dystrophy (CoRD), and Leber’s congenital amaurosis (LCA) because these lead to early developmental blindness via rod and cone photoreceptor dysfunction. The putative mutation for the Rdy phenotype is a single nucleotide deletion in the cone rod homeobox (CRX) protein, causing a frame shift that introduces a premature stop codon. Both normal CRX and rdyCRX proteins are expressed in vivo, suggesting a competitive interaction as the mechanism of pathology. The premature stop codon causes the truncation of the last third of the CRX protein containing the transactivational domains required for functional activity, while retaining the DNA binding domains allowing the rdyCRX to potentially compete with the normal CRX protein for binding to promoter regions. This could result in disrupting transcription initiation of genes necessary for the development and maintenance of the eye. EMSA analysis demonstrates competitive binding to Bat‐1 promoter oligonucleotide. Wild type CRX, rdyCRX, NRL, and NR2E3 have been successfully cloned in preparation of the development of a transcriptional activity assay.
Grant Funding Source: Supported by HHMI