Dysfunction of <i>GRAP</i> , encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss

Abstract

We have identified a <i>GRAP</i> variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. <i>GRAP</i> 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, <i>Grap</i> 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 (<i>drk</i>), the <i>Drosophila</i> homolog of human <i>GRAP</i>, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of <i>drk</i> in JO causes scolopidium abnormalities. <i>drk</i> 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 <i>GRAP</i> mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.