Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss
Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss
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DOI：
10.1073/pnas.1810951116
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发表时间：
2019-01-22
影响因子：
11.1
通讯作者：
Tekin, Mustafa
中科院分区：
文献类型：
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作者：
Li, Chong;Bademci, Guney;Tekin, Mustafa
我们在两个不相关的常染色体隐性遗传性非综合征性耳聋家系中发现了一个GRAP变异体（c.311A>T; p.GIn104Leu）。GRAP编码高度保守的生长因子受体结合蛋白2（GRB 2）/Sem-5/drk蛋白家族的成员，其参与Ras信号传导;然而，生长因子受体结合蛋白2（GRB 2）相关衔接蛋白（GRAP）在听觉系统中的功能尚不清楚。在这里，我们表明，在小鼠中，葡萄糖在内耳中表达和蛋白定位到神经纤维支配耳蜗和椭圆囊听毛细胞。受体激酶（drk）的下游是人GRAP的果蝇同源物，在约翰斯顿器官（JO）（苍蝇的听觉器官）中表达，并且JO中drk的缺失引起果蝇的异常。drk突变果蝇在负趋地性行为方面存在缺陷，这可以被人野生型而不是突变GRAP抑制。此外，drk特异性地与突触蛋白共定位在突触处，这表明此类衔接蛋白在调节神经系统中肌动蛋白细胞骨架动力学方面具有潜在作用。我们的研究结果建立了GRAP突变和非综合征性耳聋之间的因果关系，并表明GRAP/drk在听力中的功能。
We have identified a GRAP variant (c.311A>T; p.GIn104Leu) cose-gregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.