title: c-Ret-mediated hearing loss in mice with Hirschsprung disease.
abstract: A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-kappaB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans.
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Ohgami
authors.forename: Michiru
authors.initials: M
authors.lastname: Ida-Eto
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimotake
authors.forename: Naomi
authors.initials: N
authors.lastname: Sakashita
authors.forename: Michihiko
authors.initials: M
authors.lastname: Sone
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakashima
authors.forename: Keiji
authors.initials: K
authors.lastname: Tabuchi
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Hoshino
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
authors.forename: Toyonori
authors.initials: T
authors.lastname: Tsuzuki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Mayumi
authors.initials: M
authors.lastname: Jijiwa
authors.forename: Naoya
authors.initials: N
authors.lastname: Asai
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Masahide
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D003638:Deafness / Q000150:complications / Q000201:enzymology; D004789:Enzyme Activation; D055879:Gene Knock-In Techniques; D034381:Hearing Loss / Q000150:complications* / Q000151:congenital / Q000201:enzymology*; D006627:Hirschsprung Disease / Q000150:complications* / Q000201:enzymology*; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D013136:Spiral Ganglion / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure
chemical_list: D016328:NF-kappa B; D051096:Proto-Oncogene Proteins c-ret; D051057:Proto-Oncogene Proteins c-akt