NULL MUTATION OF ENDOTHELIN RECEPTOR-TYPE-B GENE IN SPOTTING LETHAL RATS CAUSES AGANGLIONIC MEGACOLON AND WHITE COAT COLOR

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 aganglioni c megacolon associated with white coat color, We found a 301-bp deleti on spanning the exon l-intron 1 junction of the EDNRB gene in sl rats, A restriction fragment length polymorphism caused by this deletion pe rfectly cosegregates with the sl phenotype, The deletion leads to prod uction of an aberrantly spliced EDNRB mRNA that lacks the coding seque nce for the first and second putative transmembrane domains of the G-p rotein-coupled receptor, Radioligand binding assays revealed undetecta ble levels of functional EDNRB in tissues from homozygous sl/sl rats, We conclude that EDNRB plays an essential role in the normal developme nt of two neural crest-derived cell lineages, epidermal melanocytes an d enteric neurons, in three mammalian species-humans, mice, and rats, The EDNRB-deficient rat may also prove valuable in defining the postna tal physiologic role of this receptor.