Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS One. 2012;7(11):e49889. doi: 10.1371/journal.pone.0049889. Epub 2012 Nov 21.
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-rhodopsin can be achieved by increasing the levels of wild type rhodopsin. These results point to promising directions in gene therapy for autosomal dominant neurodegenerative diseases caused by dominant-negative mutations.
感光细胞生物学中有两个突出的未知问题，一个是细胞大小的分子决定因素，在哺乳动物物种中，细胞大小非常均匀；另一个是与遗传性神经退行性致盲疾病（如色素性视网膜炎）相关的杆状细胞死亡的机制。我们通过在表达正常视紫红质或常染色体显性等位基因（编码带有致病 P23H 取代的视紫红质）的基因工程小鼠中进行视紫红质基因拷贝的体内滴定，解决了这两个问题。结果表明，杆状细胞外节的体积与视紫红质基因表达成正比；最常见的视紫红质基因突变等位基因 P23H-视紫红质通过显性负性机制导致细胞死亡；通过增加野生型视紫红质的水平，可以实现携带 P23H-视紫红质的杆状细胞的长期存活。这些结果为治疗由显性负性突变引起的常染色体显性神经退行性疾病的基因治疗指明了有希望的方向。
