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

Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1347-1352. doi: 10.1073/pnas.1810951116.

Chong Li ¹, Guney Bademci ², Asli Subasioglu ³, Oscar Diaz-Horta ², Yi Zhu ¹, Jiaqi Liu ⁴, Timothy Gavin Mitchell ¹, Clemer Abad ², Serhat Seyhan ², Duygu Duman ⁵, Filiz Basak Cengiz ², Suna Tokgoz-Yilmaz ⁶, Susan H Blanton ² ⁷ ⁸, Amjad Farooq ⁹, Katherina Walz ² ⁷, R Grace Zhai ¹⁰ ⁴, Mustafa Tekin ¹¹ ⁷ ⁸

Affiliations

1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136.
2 John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136.
3 Department of Medical Genetics, Izmir Ataturk Education and Research Hospital, 35360 Izmir, Turkey.
4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, 264005 Yantai, Shandong, China.
5 Division of Pediatric Genetics, Ankara University School of Medicine, 06260 Ankara, Turkey.
6 Department of Audiology, Ankara University School of Medicine, 06260 Ankara, Turkey.
7 Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136.
8 Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136.
9 Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136.
10 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136; gzhai@med.miami.edu mtekin@med.miami.edu.
11 John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; gzhai@med.miami.edu mtekin@med.miami.edu.

PMID: 30610177 DOI: 10.1073/pnas.1810951116

Abstract

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating 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.

Keywords

Drosophila; GRAP; adaptor proteins; drk; nonsyndromic hearing loss.

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