c-Ret-mediated hearing loss in mice with Hirschsprung disease.
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.
Ohgami
Nobutaka
N
Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan.
Ida-Eto
Michiru
M
Shimotake
Takashi
T
Sakashita
Naomi
N
Sone
Michihiko
M
Nakashima
Tsutomu
T
Tabuchi
Keiji
K
Hoshino
Tomofumi
T
Shimada
Atsuyoshi
A
Tsuzuki
Toyonori
T
Yamamoto
Masahiko
M
Sobue
Gen
G
Jijiwa
Mayumi
M
Asai
Naoya
N
Hara
Akira
A
Takahashi
Masahide
M
Kato
Masashi
M
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
D016328:NF-kappa B; D051096:Proto-Oncogene Proteins c-ret; D051057:Proto-Oncogene Proteins c-akt