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

Chong Li, Guney Bademci, Asli Subasioglu, Oscar Diaz-Horta, Yi Zhu, Jiaqi Liu, Timothy Gavin Mitchell, Clemer Abad, Serhat Seyhan, Duygu Duman, Filiz Basak Cengiz, Suna Tokgoz-Yilmaz, Susan H Blanton, Amjad Farooq, Katherina Walz, Rong G Zhai, Mustafa Tekin

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)1347-1352
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number4
DOIs
StatePublished - Jan 22 2019

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GRB2 Adaptor Protein
Sensorineural Hearing Loss
Phosphotransferases
Proteins
Auditory Hair Cells
Synapsins
Cochlea
Inner Ear
Actin Cytoskeleton
Hearing Loss
Diptera
Synapses
Protein Kinases
Nervous System
Hearing
Drosophila

Keywords

  • Adaptor proteins
  • Drk
  • Drosophila
  • GRAP
  • Nonsyndromic hearing loss

ASJC Scopus subject areas

  • General

Cite this

Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss. / Li, Chong; Bademci, Guney; Subasioglu, Asli; Diaz-Horta, Oscar; Zhu, Yi; Liu, Jiaqi; Mitchell, Timothy Gavin; Abad, Clemer; Seyhan, Serhat; Duman, Duygu; Cengiz, Filiz Basak; Tokgoz-Yilmaz, Suna; Blanton, Susan H; Farooq, Amjad; Walz, Katherina; Zhai, Rong G; Tekin, Mustafa.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 4, 22.01.2019, p. 1347-1352.

Research output: Contribution to journalArticle

Li, Chong ; Bademci, Guney ; Subasioglu, Asli ; Diaz-Horta, Oscar ; Zhu, Yi ; Liu, Jiaqi ; Mitchell, Timothy Gavin ; Abad, Clemer ; Seyhan, Serhat ; Duman, Duygu ; Cengiz, Filiz Basak ; Tokgoz-Yilmaz, Suna ; Blanton, Susan H ; Farooq, Amjad ; Walz, Katherina ; Zhai, Rong G ; Tekin, Mustafa. / Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 4. pp. 1347-1352.
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AU - Li, Chong

AU - Bademci, Guney

AU - Subasioglu, Asli

AU - Diaz-Horta, Oscar

AU - Zhu, Yi

AU - Liu, Jiaqi

AU - Mitchell, Timothy Gavin

AU - Abad, Clemer

AU - Seyhan, Serhat

AU - Duman, Duygu

AU - Cengiz, Filiz Basak

AU - Tokgoz-Yilmaz, Suna

AU - Blanton, Susan H

AU - Farooq, Amjad

AU - Walz, Katherina

AU - Zhai, Rong G

AU - Tekin, Mustafa

PY - 2019/1/22

Y1 - 2019/1/22

N2 - We have identified a GRAP variant (c.311A>T; p.Gln104Leu) 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.

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

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KW - Nonsyndromic hearing loss

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