Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color
Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color
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DOI：
10.1073/pnas.93.2.867
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发表时间：
1996-01-23
影响因子：
11.1
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
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作者：
Gariepy, CE;Cass, DT;Yanagisawa, M
在小鼠和人类中，编码内皮素受体B型（EDNRB）的基因突变会产生先天性神经节巨结肠和色素异常。在斑点致死（sr）大鼠中，我们报道了EDNRB基因自然发生的零突变，这些大鼠表现出与白色毛色相关的神经节巨结肠。我们发现在sl大鼠中，EDNRB基因的外显子l内含子1连接处有301 bp的缺失。这种缺失导致的限制性片段长度多态性与sl表型完全共分离，缺失导致产生异常剪接的EDNRB mRNA，缺乏g蛋白偶联受体的第一和第二假定跨膜结构域的编码序列，放射配体结合分析显示，在纯合子sl/sl大鼠的组织中检测不到功能性EDNRB的水平。我们得出结论，EDNRB在三种哺乳动物物种（人类、小鼠和大鼠）的两种神经嵴来源的细胞系（表皮黑色素细胞和肠神经元）的正常发育中起着至关重要的作用。EDNRB缺失的大鼠也可能在确定该受体的出生后生理作用方面证明有价值。
Mutations in the gene encoding the endothelin receptor type B (EDNRB) produce congenital aganglionic megacolon and pigment abnormalities in mice and humans, Here we report a naturally occurring null mutation of the EDNRB gene in spotting lethal (sr) rats, which exhibit aganglionic megacolon associated with white coat color, We found a 301-bp deletion spanning the exon l-intron 1 junction of the EDNRB gene in sl rats, A restriction fragment length polymorphism caused by this deletion perfectly cosegregates with the sl phenotype, The deletion leads to production of an aberrantly spliced EDNRB mRNA that lacks the coding sequence for the first and second putative transmembrane domains of the G-protein-coupled receptor, Radioligand binding assays revealed undetectable levels of functional EDNRB in tissues from homozygous sl/sl rats, We conclude that EDNRB plays an essential role in the normal development of two neural crest-derived cell lineages, epidermal melanocytes and enteric neurons, in three mammalian species-humans, mice, and rats, The EDNRB-deficient rat may also prove valuable in defining the postnatal physiologic role of this receptor.