Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice.
Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice.
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DOI：
10.1186/1471-2202-9-74
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发表时间：
2008-07-31
期刊：
影响因子：
2.4
通讯作者：
Nickells RW
中科院分区：
文献类型：
--
作者：
Dietz JA;Li Y;Chung LM;Yandell BS;Schlamp CL;Nickells RW
神经元胞体的内源性凋亡是遗传背景影响神经退行性疾病的一个方面。影响这一过程的基因可能作为易感等位基因，导致这些疾病的复杂遗传性质。视网膜神经节细胞死亡是慢性和遗传复杂的神经退行性疾病青光眼的定义特征。以前的研究使用视神经挤压程序在近交系小鼠中，表明神经节细胞抗挤压受到1-2个预测位点的孟德尔显性遗传的影响。为了进一步评估这一点，我们繁殖和表型的F2小鼠从一个抗性近交系（DBA/2 J）和一个敏感的品系（BALB/cByJ）衍生的大人口。使用微卫星标记对F2小鼠进行全基因组定位，在第5号染色体上的25 cM（58 Mb）间隔（Chr5.loc34-59 cM）检测到一个高度显著的数量性状位点。在该屏幕的分辨率下未检测到相互作用的基因座。我们将该位点命名为视网膜神经节细胞易感1，Rgcs 1。该区域的计算机分析揭示了578个基因或表达序列标签的存在，其中4个在哺乳动物视网膜的神经节细胞层中高度表达，其中2个是慢性神经退行性疾病的疑似易感等位基因。此外，25个基因含有36个已知的单核苷酸多态性，这些多态性在两个亲本菌株之间产生非同义氨基酸变化。总的来说，这项分析已经确定了7个可能影响神经节细胞死亡的潜在候选基因。神经节细胞死亡的过程可能是青光眼易感性的许多方面之一。一个新的优势位点已被确定，影响视神经节细胞的敏感性挤压。负责这种敏感性的等位基因也可能是青光眼的易感性等位基因。
Intrinsic apoptosis of neuronal somas is one aspect of neurodegenerative diseases that can be influenced by genetic background. Genes that affect this process may act as susceptibility alleles that contribute to the complex genetic nature of these diseases. Retinal ganglion cell death is a defining feature of the chronic and genetically complex neurodegenerative disease glaucoma. Previous studies using an optic nerve crush procedure in inbred mice, showed that ganglion cell resistance to crush was affected by the Mendelian-dominant inheritance of 1–2 predicted loci. To assess this further, we bred and phenotyped a large population of F2 mice derived from a resistant inbred strain (DBA/2J) and a susceptible strain (BALB/cByJ). Genome wide mapping of the F2 mice using microsatellite markers, detected a single highly significant quantitative trait locus in a 25 cM (58 Mb) interval on chromosome 5 (Chr5.loc34-59 cM). No interacting loci were detected at the resolution of this screen. We have designated this locus as Retinal ganglion cell susceptible 1, Rgcs1. In silico analysis of this region revealed the presence of 578 genes or expressed sequence tags, 4 of which are highly expressed in the ganglion cell layer of the mammalian retina, and 2 of which are suspected susceptibility alleles in chronic neurodegenerative diseases. In addition, 25 genes contain 36 known single nucleotide polymorphisms that create nonsynonymous amino acid changes between the two parental strains. Collectively, this analysis has identified 7 potential candidate genes that may affect ganglion cell death. The process of ganglion cell death is likely one of the many facets of glaucoma susceptibility. A novel dominant locus has been identified that affects sensitivity of ganglion cells to optic nerve crush. The allele responsible for this sensitivity may also be a susceptibility allele for glaucoma.
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