c-Ret-mediated hearing loss in mice with Hirschsprung disease
c-Ret-mediated hearing loss in mice with Hirschsprung disease
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DOI：
10.1073/pnas.1004520107
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发表时间：
2010-07-20
影响因子：
11.1
通讯作者：
Kato, Masashi
中科院分区：
文献类型：
--
作者：
Ohgami, Nobutaka;Ida-Eto, Michiru;Kato, Masashi
有报道称，由内皮素受体B型和SOX10引起的巨结肠病（HSCR）患者显性感音神经性耳聋的风险显著增加。尽管c-RET是HSCR最常见的致病基因，但尚不清楚c-RET和c-RET的损伤是否会导致小鼠和人类的先天性耳聋。在这里，我们发现c-Ret酪氨酸1062位点磷酸化受损导致c-Ret敲入（KI）小鼠的hsr相关综合征先天性耳聋。耳聋涉及螺旋神经节神经元（SGNs）的神经变性，不仅Akt和NF-kappa B的磷酸化受损，内耳calbindin D28k的表达降低。引入组成型激活的RET可挽救c-Ret KI小鼠中伴有sgn神经退行性变的先天性耳聋。结合我们对3例先天性耳聋伴c-Ret介导的重度HSCR患者的研究结果，我们的研究结果表明，c-Ret和c-Ret是小鼠和人类耳聋相关分子。
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-kappa B 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.