title: Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations.
abstract: Hirschsprung disease (HSCR) is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. However, it remains unknown whether the single complete deletion of important HSCR-associated genes is sufficient to result in HSCR disease. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl) mutations. Moreover, we found that this mutation results in serious congenital sensorineural deafness, and these strains may be used as ideal models of Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same changed genetic background modifies three features of WS4 syndrome, aganglionosis, hearing loss, and pigment disorder in these congenic strains. We found that the same genetic background markedly changed the aganglionosis, but resulted in only slight changes to hearing loss and pigment disorder. This provided the important evidence, in support of previous studies, that different lineages of neural crest-derived cells migrating along with various pathways are regulated by different signal molecules. This study will help us to better understand complicated diseases such as HSCR and WS4 syndrome.
authors.affiliation: Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Dang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Torigoe
authors.forename: Sari
authors.initials: S
authors.lastname: Suzuki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Kanako
authors.initials: K
authors.lastname: Moritoh
authors.forename: Nobuya
authors.initials: N
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Agui
mesh_terms: D000818:Animals; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D044023:Receptor, Endothelin B / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics
chemical_list: D044023:Receptor, Endothelin B