Dominant cone-rod dystrophy: a mouse model generated by gene targeting of the GCAP1/Guca1a gene.
Dominant cone-rod dystrophy: a mouse model generated by gene targeting of the GCAP1/Guca1a gene.
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DOI：
10.1371/journal.pone.0018089
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发表时间：
2011-03-28
期刊：
影响因子：
3.7
通讯作者：
Hunt DM
中科院分区：
文献类型：
--
作者：
Buch PK;Mihelec M;Cottrill P;Wilkie SE;Pearson RA;Duran Y;West EL;Michaelides M;Ali RR;Hunt DM
锥体营养不良3 （COD3）是一种严重的显性遗传性视网膜变性，由编码鸟苷酸环化酶激活蛋白1 （GCAP1）的基因GUCA1A错义突变引起。GCAP1在控制光感受器环核苷酸水平中的作用已经在很大程度上通过敲除小鼠得到了阐明，但这些小鼠的疾病病理不能直接推断为COD3，因为这涉及GCAP1功能的改变，而不是丧失。因此，为了评估这种显性疾病的病理学，我们在小鼠Guca1a基因中引入了一个点突变，导致E155G氨基酸替代；这是在COD3患者中发现的一种致病突变。这种新型锥体营养不良小鼠模型的疾病进展是通过多种技术确定的，包括视网膜电图（ERG）、视网膜组织学、免疫组织化学和cGMP水平测量。虽然视网膜发育在3个月前是正常的，但随后视网膜功能逐渐下降，锥体反应的变化远远大于杆状反应，并伴有相应的光感受器的丧失。此外，我们已经证明，环状GMP的积累先于观察到的视网膜变性，并可能有助于疾病机制。重要的是，这种敲入突变小鼠具有许多与人类疾病相同的特征，从而使其成为进一步探索疾病发病机制和研究治疗干预措施的优秀模型。
Cone dystrophy 3 (COD3) is a severe dominantly inherited retinal degeneration caused by missense mutations in GUCA1A, the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1). The role of GCAP1 in controlling cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in COD3 patients. Disease progression in this novel mouse model of cone dystrophy was determined by a variety of techniques including electroretinography (ERG), retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although retinal development was normal up to 3 months of age, there was a subsequent progressive decline in retinal function, with a far greater alteration in cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of cyclic GMP precedes the observed retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions.
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影响因子：
5.5
作者：
Hetling, JR;Pepperberg, DR
通讯作者：
Pepperberg, DR
影响因子：
11.4
作者：
Howes, KA;Pennesi, ME;Baehr, W
通讯作者：
Baehr, W
影响因子：
4.8
作者：
He, LH;Poblenz, AT;Fox, DA
通讯作者：
Fox, DA
影响因子：
1.8
作者：
Jiang, Li;Wheaton, Dianna;Bereta, Grzegorz;Zhang, Kang;Palczewski, Krzysztof;Birch, David G.;Baehr, Wolfgang
通讯作者：
Baehr, Wolfgang
DOI：
10.1073/pnas.85.1.94
发表时间：
1988-01-01
影响因子：
11.1
作者：
HANKE, W;COOK, NJ;KAUPP, UB
通讯作者：
KAUPP, UB