Human Disease Model Report: deafness, autosomal recessive 114

General Information

Name

deafness, autosomal recessive 114

FlyBase ID

FBhh0000986

Disease Ontology Term

autosomal recessive nonsyndromic deafness 114

Parent Disease

deafness, autosomal recessive

OMIM

DEAFNESS, AUTOSOMAL RECESSIVE 114; DFNB114

Overview

A variant of GRAP was identified as cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP (GRB2-Related Adapter Protein) is a member of the GRB2/Sem5/Drk family; it is a cytoplasmic adaptor protein and is known to impact the Ras signaling pathway. There are three paralogous genes in human, including GRB2 (growth factor receptor bound protein 2). There is a single fly gene in this family, drk, for which loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Several UAS constructs of human Hsap\GRAP have been introduced into flies, including wild-type and the identified variant. Partial heterologous rescue (functional complementation) has been demonstrated: wild-type Hsap\GRAP reduces the negative geotaxis defect observed for Dmel\drk compound heterozygous adults. The construct carrying the implicated variant fails to rescue. Variant(s) implicated in human disease tested (as transgenic human gene, GRAP): the Q104L variant form has been introduced into flies.

Animals homozygous for loss-of-functions mutations of Dmel\drk typically die during the larval or pupal stage. For some alleles, olfactory association learning is lower in heterozygous animals compared to controls. Carrying a biallelic combination that is semi-lethal, compound heterozygous adults exhibit defects in negative geotaxis. The gene is expressed in embryos and in multiple tissues at later stages, including the adult brain, photoreceptor cells and Johnston's organ; Johnston's organ is the component of the Drosophila auditory system required for sensing gravity, wind flow, and near-field sound. Many physical and genetic interactions have been described for Dmel\drk; see below and in the drk gene report.

[updated Mar. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: deafness, autosomal recessive

Symptoms and phenotype

Specific Disease Summary: deafness, autosomal recessive 114

OMIM report

[DEAFNESS, AUTOSOMAL RECESSIVE 114; DFNB114](https://omim.org/entry/618456)

Human gene(s) implicated

[GRB2-RELATED ADAPTOR PROTEIN; GRAP](https://omim.org/entry/604330)

Symptoms and phenotype

DFNB114 is characterized by congenital profound sensorineural hearing loss (Li et al., 2019; pubmed:30610177). [from MIM:618456; 2019.10.28]

(OMIM, 2013-)

Profound sensorineural hearing loss without other observed morbidities (FBrf0241287).

(FlyBase Curators, 2013-)

Genetics

Family pedigrees are consistent with autosomal recessive inheritance (FBrf0241287).

(FlyBase Curators, 2013-)

Autosomal recessive deafness-114 (DFNB114) is caused by homozygous mutation in the GRAP gene. [from MIM:618456; 2019.10.28]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

GRAP (GRB2-Related Adapter Protein) encodes a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains; it is a member of the GRB2/Sem5/Drk family. Among other roles, it couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. [Gene Cards, GRAP; 2019.03.15]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): GRAP
Gene Cards: GRAP
MedlinePlus (gene): GRAP
MARRVEL (human gene): GRAP
NCBI (Entrez) gene: GRAP; GRB2 related adaptor protein

Disease synonyms

deafness, non-syndromic (postulated), GRAP-related

DFNB114

hearing loss, GRAP-related

non-syndromic hearing loss

Related Diseases

Related human health report(s)

deafness, autosomal recessive

Related Specific Diseases

OMIM phenotypic series

Deafness, autosomal recessive

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[DFNB2](https://omim.org/entry/600060)

[MYO7A](https://omim.org/entry/276903)

deafness, autosomal recessive 2

[DFNB23](https://omim.org/entry/609533)

[PCDH15](https://omim.org/entry/605514)

[DFNB36](https://omim.org/entry/609006)

[ESPN](https://omim.org/entry/606351)

deafness, autosomal recessive 36

[DFNB48](https://omim.org/entry/609439)

[CIB2](https://omim.org/entry/605564)

deafness, autosomal recessive 48

[DFNB67](https://omim.org/entry/610265)

[LHFPL5](https://omim.org/entry/609427)

deafness, autosomal recessive 67

[DFNB114](https://omim.org/entry/618456)

[GRAP](https://omim.org/entry/604330)

deafness, autosomal recessive 114

Ortholog Information

Human gene(s) in FlyBase

Hsap\GRAP

Human gene (HGNC)

Symbol / Name

GRAP; GRB2 related adaptor protein

D. melanogaster ortholog (based on DIOPT)

Dmel\drk

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 4 human to 1 Drosophila. The human genes are GRB2, GRAP, GRAP2, and GRAPL.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\drk

Gene Snapshot

downstream of receptor kinase (drk) encodes an adaptor protein that recognizes phosphorylated tyrosine residues of membrane receptors and triggers the Ras/Raf/MAPK pathway. drk product contributes to the regulation of cytoskeletal organization and participates in developmental and cognitive processes (associative learning, anesthesia resistant memory). [Date last reviewed: 2018-09-06]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human GRB2, GRAP, GRAP2, and GRAPL (1 Drosophila to 4 human). Dmel\drk shares 65% identity and 78% similarity with GRB2; shares 54% identity and 68% similarity with GRAP.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (58 groups)

drk

RNA-protein

Interacting group

Assay

References

drk - pum

rna three hybrid

(Kim et al., 2012)

protein-protein

Interacting group

Assay

References

drk - 14-3-3ε

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - 14-3-3ζ

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Ack

anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot

(Schoenherr et al., 2012)

drk - Ack-like

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - ATPsynβ

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - C3G

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Cad96Ca

two hybrid, pull down, anti tag western blot

(Tsarouhas et al., 2014)

drk - Cbl

anti bait coimmunoprecipitation, western blot, pull down, autoradiography, two hybrid

(Wang and Pai, 2011, Robertson et al., 2000)

drk - CG1806

experimental knowledge based

(Guruharsha et al., 2011)

drk - CG5004

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - CG5568

experimental knowledge based

(Guruharsha et al., 2011)

drk - CG6769

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

drk - CG18659

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - CG42788

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - cindr

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - cno

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Cortactin

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - csw

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Cyfip

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Dab

lambda phage display, autoradiography, anti tag coimmunoprecipitation, western blot, pull down, peptide massfingerprinting, anti bait coimmunoprecipitation

(Friedman et al., 2011, Le and Simon, 1998)

drk - DIP2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - dl

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Dld

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Dlst

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - dos

nuclear magnetic resonance, pull down, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot

(Sayeesh et al., 2023, Sayeesh et al., 2022, Friedman et al., 2011, Feller et al., 2002)

drk - Egfr

two hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot, pull down

(Friedman et al., 2011, Wang and Pai, 2011, Bianco et al., 2007, MacDougall et al., 2004, Lai et al., 1995, Schweitzer et al., 1995)

drk - ena

pull down, western blot

(Ahern-Djamali et al., 1999)

drk - ex

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

drk - Hexo1

experimental knowledge based

(Guruharsha et al., 2011)

drk - jub

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - lark

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - loco

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Mec2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - mim

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - moody

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - mop

experimental knowledge based

(Guruharsha et al., 2011)

drk - msn

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Nin

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Pez

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Friedman et al., 2011, Guruharsha et al., 2011)

drk - Pi3K68D

pull down, western blot

(MacDougall et al., 2004)

drk - pico

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - pins

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Pkn

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Pvr

two hybrid, anti tag coimmunoprecipitation, peptide massfingerprinting, anti tag western blot

(Friedman et al., 2011, Bianco et al., 2007, Ishimaru et al., 2004)

drk - pyd

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Raf

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - RhoGAP15B

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - RhoGAP18B

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - RhoGEF2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - sav

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

drk - sev

anti bait coimmunoprecipitation, western blot, nuclear magnetic resonance, fluorescent resonance energy transfer, fluorescence microscopy, pull down

(Sayeesh et al., 2024, Almudi et al., 2010, Olivier et al., 1993)

drk - Shc

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - shi

anti tag coimmunoprecipitation, peptide massfingerprinting, pull down, autoradiography

(Friedman et al., 2011, Robertson et al., 2000)

drk - Sos

nuclear magnetic resonance, pull down, western blot, isothermal titration calorimetry, predetermined participant, anti tag coimmunoprecipitation, peptide massfingerprinting, far western blotting, lambda phage display, autoradiography

(Sayeesh et al., 2023, Thole et al., 2023, Sayeesh et al., 2022, Friedman et al., 2011, Le and Simon, 1998, Olivier et al., 1993)

drk - sty

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Synj

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

drk - Vps37B

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)

drk