title: Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.
abstract: 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 (sl) rats, which exhibit aganglionic megacolon associated with white coat color. We found a 301-bp deletion spanning the exon 1-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.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas 75235-9050, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Gariepy
authors.forename: D T
authors.initials: DT
authors.lastname: Cass
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D003106:Colon / Q000294:innervation / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D016232:Endothelins / Q000378:metabolism; D005724:Ganglia / Q000473:pathology*; D005804:Genes, Lethal; D006197:Hair / Q000002:abnormalities; D006579:Heterozygote; D006720:Homozygote; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D051381:Rats; D011922:Rats, Mutant Strains; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D018076:DNA, Complementary; D016232:Endothelins; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin