The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals

Li, Tongchao; Γιαγτζόγλου, Νικόλαος; Eberl, Daniel F.; Jaiswal, Sonal; Cai, Tiantian; Godt, Dorothea; Groves, Andrew K.; Bellen, Hugo J.

doi:10.7554/elife.15258

Cited by 29 publications

(44 citation statements)

References 78 publications

(114 reference statements)

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“…The SH2 domains directly recognize phosphotyrosine-containing sites on activated receptor protein kinases (RTKs) and cytoplasmic proteins. It has been suggested that the adaptor proteins Grb2/ Sem-5/drk provide a functional link between RTKs and activation of Ras signaling (10,17,18). The SH3 domains, particularly those located on the amino-terminal side of Grb2/Sem-5/drk, bind the C-terminal tail of the Sos protein (8).…”

Section: Discussionmentioning

confidence: 99%

“…5B). To overcome the lethality of homozygous flies and to determine the function of drk in the JO, we generated mosaic animals (eyFLP; drk Δ ) with a homozygous deletion of drk in the antenna and the eye but heterozygous in the rest of the body through flippase/flippase recognition target (Flp/FRT)-mediated mitotic recombination using the eyFLP system (18). We observed severe locomotor deficits in mosaic flies suggesting strong defects in gravity sensing as the main reason for the climbing defects because the JO is homozygous for drk Δ whereas the body (neuromuscular tissue) is heterozygous (Fig.…”

Section: The Pgln104leu Variant Most Likely Alters Interactions Of Gmentioning

confidence: 99%

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

Bademci

Subaşıoğlu³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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.adaptor proteins | drk | Drosophila | GRAP | nonsyndromic hearing loss H earing loss (HL) is the most common sensory disorder with an incidence of 1-3 in 1,000 births (1). Genetic factors show high heterogeneity and are responsible for more than half of the cases with congenital HL (2). It is estimated that 70% of genetic HL is nonsyndromic sensorineural HL and mostly shows an autosomal recessive inheritance pattern (1, 3). The identification of DNA variants causing HL is rapidly advancing due to technological developments in genome sequencing. However, delineating causality for a novel rare variant in a gene not previously associated with HL is difficult and often requires functional studies in model organisms.The mouse has been shown to be an excellent model organism to study human deafness due to the anatomic and physiologic similarities of their auditory systems with those of humans (4). Recent studies of Drosophila's hearing organ, Johnston's organ (JO), highlight the molecular and genetic conservations of the mechanosensory transduction in flies and vertebrates (5, 6).Several key genes first identified in Drosophila, such as atonal, crinkled, and nanchung, that are required for the specification or function of auditory cell types in the JO are also important for the normal development or function of the vertebrate ear (5). In addition, 20% of Drosophila auditory-associated genes have human homologs and are implicated in hearing disorders (7).In this paper, via exome and genome sequencing of over 60 consanguineous multiplex families with autosomal recessive nonsyndromic HL, which are negative for variants in known deafness genes (details of families are given in SI Appendix, Table S1), we have identified a GRAP variant in two unrelated Turkish families. We show that G...

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Section: Discussionmentioning

confidence: 99%

Section: The Pgln104leu Variant Most Likely Alters Interactions Of Gmentioning

confidence: 99%

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

Bademci

Subaşıoğlu³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The Drosophila genome harbors homologs of several Usher genes and some of these have been characterized in Johnston's organ ( Table 2 ). The Drosophila homolog of myosin VIIA [ myosin VIIA ; also known as crinkled ( ck )] is required for hearing: loss of ck abolishes a fly's auditory responses and causes the scolopidia to detach from the cuticle of the a2/a3 antennal joint in Johnston's organ ( Li et al, 2016 ; Todi et al, 2005 , 2008 ) ( Fig. 4 ).…”

Section: Conservation Of Usher Syndrome Proteins and Their Interactiomentioning

confidence: 99%

UsingDrosophilato study mechanisms of hereditary hearing loss

Bellen

Groves

2018

Disease Models &Amp; Mechanisms

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Johnston's organ – the hearing organ of Drosophila – has a very different structure and morphology to that of the hearing organs of vertebrates. Nevertheless, it is becoming clear that vertebrate and invertebrate auditory organs share many physiological, molecular and genetic similarities. Here, we compare the molecular and cellular features of hearing organs in Drosophila with those of vertebrates, and discuss recent evidence concerning the functional conservation of Usher proteins between flies and mammals. Mutations in Usher genes cause Usher syndrome, the leading cause of human deafness and blindness. In Drosophila, some Usher syndrome proteins appear to physically interact in protein complexes that are similar to those described in mammals. This functional conservation highlights a rational role for Drosophila as a model for studying hearing, and for investigating the evolution of auditory organs, with the aim of advancing our understanding of the genes that regulate human hearing and the pathogenic mechanisms that lead to deafness.

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“…With regard to renal manifestations, it has been shown that MYH9 mutations affect podocytes attaching to the basement membrane through focal adhesion formation and result in their detachment, which is the main cause of proteinuria . Finally, functional myosin IIA is required to ensure that sensory cells in the inner ear respond correctly to sound by detecting air vibrations and converting them into electrical impulses .…”

Section: Essential Features Of Inherited Thrombocytopaenias Predisposmentioning

confidence: 99%

Bleeding is not the main clinical issue in many patients with inherited thrombocytopaenias

2017

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Bleeding diathesis has been considered for a long time the main clinical issue impacting the lives of patients affected by inherited thrombocytopaenias. However, the number of known inherited thrombocytopaenias greatly increased in recent years, and careful evaluation of hundreds of patients affected by these 'new' disorders revealed that most of them are at risk of developing additional life-threatening disorders during childhood or adult life. These additional disorders are usually more serious and dangerous than low platelet count. For instance, it is known that mutations in RUNX1, ANKRD26 and ETV6 cause congenital thrombocytopaenia, but we now know that they also predispose to haematological malignancies. Similarly, MYH9 mutations result in congenital thrombocytopaenia and increase the risk of developing kidney failure, cataracts and hearing loss at a later stage, while MPL mutations cause a congenital thrombocytopaenia that almost always evolves into deadly bone marrow failure. Thus, identification of patients with these disorders is essential for evaluation of their prognosis, enabling effective genetic counselling, personalizing follow-up and giving appropriate treatments in case of development of additional diseases. Careful clinical evaluation and peripheral blood film examination are extremely useful tools in guiding the diagnostic process and identifying the candidate genes to be sequenced.

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The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals

Cited by 29 publications

References 78 publications

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

UsingDrosophilato study mechanisms of hereditary hearing loss

Bleeding is not the main clinical issue in many patients with inherited thrombocytopaenias

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