rhodopsin gene expression determines rod outer segment size and rod cell resistance to a dominant-negative neurodegeneration mutant视紫红质基因表达确定杆外节大小,视杆细胞抵抗显性负神经退行性变的突变体.pdfVIP

Rhodopsin Gene Expression Determines Rod Outer Segment Size and Rod Cell Resistance to a Dominant- Negative Neurodegeneration Mutant 1,2¤ 1 1 3 1,4 Brandee A. Price , Ivette M. Sandoval , Fung Chan , Ralph Nichols , Ramon Roman-Sanchez , Theodore G. Wensel1,3,4, John H. Wilson1,2,4* 1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America, 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States of America, 4 Graduate Program in Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America Abstract Two outstanding unknowns in the biology of photoreceptors are the molecular determinants of cell size, which is remarkably uniform among mammalian species, and the mechanisms of rod cell death associated with inherited neurodegenerative blinding diseases such as retinitis pigmentosa. We have addressed both questions by performing an in vivo titration with rhodopsin gene copies in genetically engineered mice that express only normal rhodopsin or an autosomal dominant allele, encoding rhodopsin with a disease-causing P23H substitution. The results reveal that the volume of the rod outer segment is proportional to rhodopsin gene expression; that P23H-rhodopsin, the most common rhodopsin gene disease allele, causes cell death via a dominant-negative mechanism; and that long term survival of rod cells carrying P23H-