title: A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene.
abstract: Waardenburg syndrome (WS) is a hereditary auditory-pigmentary syndrome with hearing impairment and pigmentation anomaly of the skin and iris. In addition to these major symptoms, WS type 4 is associated with Hirschsprung disease. To date, three genes responsible for WS4 have been cloned: genes for a transcription factor SOX10, endothelin 3 (EDN3), and endothelin B receptor (EDNRB). We here describe a novel mutant mouse with a mutation of the Ednrb gene, and propose the mouse as an animal model of WS4. These mutants are with mixed genetic background of BALB/c and MSM (an inbred strain of Japanese wild mice) and have extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon: their colon distal to the megacolon lacked Auerbach's plexus cells. Interestingly, these mutants did not respond to sound, and the stria vascularis of their cochlea lacked intermediate cells, i.e., neural crest-derived melanocytes. Since these symptoms resembled those of human WS4 and were transmitted in autosomal recessive hereditary manner, the mutants were named WS4 mice. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis revealed that their Ednrb lacked 318 nucleotides encoding Ednrb transmembrane domains owing to deletion of exons 2 and 3. Interaction between endothelin 3 and its receptor is required for normal differentiation and development of melanocytes and Auerbach's plexus cells. We concluded that a missing interaction here led to a lack of these cells, which caused pigmentation anomaly, deafness, and megacolon in WS4 mice.
authors.affiliation: Saitama Cancer Center, Research Institute 818 Komuro, Ina, Saitama 362-0806, Japan.
authors.forename: Yoshibumi
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shinkai
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Michihiro
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tachibana
mesh_terms: D000818:Animals; D003051:Cochlea / Q000002:abnormalities / Q000473:pathology; D018076:DNA, Complementary / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D003638:Deafness / Q000235:genetics*; D004195:Disease Models, Animal; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D008531:Megacolon / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D051739:Microphthalmia-Associated Transcription Factor; D009154:Mutation; D010641:Phenotype; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000145:classification / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014157:Transcription Factors