Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat
Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat
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DOI：
10.1093/hmg/9.4.645
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发表时间：
2000-03-01
影响因子：
3.5
通讯作者：
Vollrath, D
中科院分区：
文献类型：
--
作者：
D'Cruz, PM;Yasumura, D;Vollrath, D
脊椎动物感光细胞是视网膜的基本感觉器官，能够将吸收的光子的能量转化为神经元信号。哺乳动物感光细胞外节的近端部分每天由细胞体合成，并且外节尖端以昼夜节律脱落，导致外节大约每9天完全更新，脱落的外节被相邻的视网膜色素上皮（RPE）细胞吞噬，代谢物再循环到光感受器。皇家外科学院（RCS）大鼠是一种广泛研究的，视网膜色素上皮细胞不能吞噬脱落的外节，感光细胞随后死亡。我们用位置克隆的方法研究了rdy在0.3cM的遗传包含区间内，我们发现了RCS DNA的小缺失，其破坏了编码受体酪氨酸激酶Mertk的基因。该缺失包括Mertk的第二编码外显子上游的剪接受体位点，并导致缺少该外显子的缩短的转录物，异常转录本连接第一和第三编码外显子，导致在AUG后20个密码子的移码和翻译终止信号。这些和其他数据的一致性表明Mertk可能是rdy的基因，我们的研究结果为受体酪氨酸激酶在一种特殊形式的吞噬作用中的重要作用提供了遗传学证据，并提出了一种分子模型用于RPE细胞摄取外节。
Vertebrate photoreceptor cells are the basic sensory apparatus of the retina, capable of converting the energy of absorbed photons into neuronal signals, The proximal portions of mammalian photoreceptor outer segments are synthesized daily by cell bodies, and outer segment tips are shed with a circadian rhythm, resulting in a complete turnover of outer segments about every 9 days, The shed outer segments are phagocytosed by adjacent retinal pigment epithelial (RPE) cells, and metabolites are recycled to photoreceptors, The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the RPE fails to phagocytose shed outer segments, and photoreceptor cells subsequently die. We have used a positional cloning approach to study the rdy (retinal dystrophy) locus of the RCS rat, Within a 0.3 cM genetic inclusion interval, we have discovered a small deletion of RCS DNA that disrupts the gene encoding the receptor tyrosine kinase Mertk, The deletion includes the splice acceptor site upstream of the second coding exon of Mertk and results in a shortened transcript that lacks this exon, The aberrant transcript joins the first and third coding exons, leading to a frameshift and a translation termination signal 20 codons after the AUG, The concordance of these and other data indicate that Mertk is probably the gene for rdy, Our results provide genetic evidence for an essential role of a receptor tyrosine kinase in a specialized form of phagocytosis and suggest a molecular model for ingestion of outer segments by RPE cells.