Genetics, pathogenesis and therapeutic developments for Usher syndrome type 2

Stemerdink, Merel; García‐Bohórquez, Belén; Schellens, Renske; García‐García, Gema; Wijk, Erwin van; Millán, José María

doi:10.1007/s00439-021-02324-w

Cited by 21 publications

(20 citation statements)

References 194 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data indicate an important role of VLGR1 in retinal photoreceptor cell function. This is further strengthened by the fact that mutations in the VLGR1 gene cause USH2C, which is also characterized by a strong ocular component leading to vision loss [ 4 ]. As already discussed above, VLGR1 TAPs indicate the interaction with proteins associated with syndromic and non-syndromic retinal ciliopathies, such as KIF11 [ 91 ], Nephrocystin 5 (IQCB1/NPHP5), associated with Senior-Løken syndrome [ 92 ], and Retinitis pigmentosa 1 (RP1), the product of the autosomal dominant Retinitis pigmentosa RP1 gene [ 93 , 94 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1

Knapp

Roedig

et al. 2022

Molecules

View full text Add to dashboard Cite

The very large G-protein-coupled receptor 1 (VLGR1/ADGRV1) is the largest member of the adhesion G-protein-coupled receptor (ADGR) family. Mutations in VLGR1/ADGRV1 cause human Usher syndrome (USH), a form of hereditary deaf-blindness, and have been additionally linked to epilepsy. In the absence of tangible knowledge of the molecular function and signaling of VLGR1, the pathomechanisms underlying the development of these diseases are still unknown. Our study aimed to identify novel, previously unknown protein networks associated with VLGR1 in order to describe new functional cellular modules of this receptor. Using affinity proteomics, we have identified numerous new potential binding partners and ligands of VLGR1. Tandem affinity purification hits were functionally grouped based on their Gene Ontology terms and associated with functional cellular modules indicative of functions of VLGR1 in transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance. In addition, we validated the identified protein interactions and pathways in vitro and in situ. Our data provided new insights into possible functions of VLGR1, related to the development of USH and epilepsy, and also suggest a possible role in the development of other neuronal diseases such as Alzheimer’s disease.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Mutations in VLGR1/ADGRV1 can manifest in two disease phenotypes. Most VLGR1 mutations are causative for the human Usher syndrome type 2C (USH2C) [ 4 ]. Usher syndrome (USH) is a severe genetically heterogenous autosomal recessive disorder and the most common cause of hereditary deaf-blindness [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1

Knapp

Roedig

et al. 2022

Molecules

View full text Add to dashboard Cite

show abstract

“…For example, different combinations of pathogenic USH2A variants can result in Usher syndrome type 2, consisting of retinitis pig-mentosa (RP) and hearing impairment, non-syndromic RP (USH2A [MIM: 276901]), or even no phenotype. [1][2][3] Another important illustration of autosomal recessive inheritance with a wide phenotypic spectrum was observed for CFTRassociated diseases. Cystic fibrosis (CF [MIM: 219700]) is caused by bi-allelic variants in CFTR.…”

Section: Introductionmentioning

confidence: 99%

Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity

Cornelis¹,

Runhart²,

Bauwens³

et al. 2022

The American Journal of Human Genetics

View full text Add to dashboard Cite

“…The occurrence of vestibular dysfunction in some USH2 patients warrants further investigation. Indeed, defective vestibular responses were reported in eight of eleven USH2 patients tested in one study, but the lack of a clear genetic diagnosis for these patients precluded the identification of a direct causal role of USH2 ( 171 , 173 ).…”

Section: Detailed Mechanisms Of Vestibular Function: Insight From Ani...mentioning

confidence: 99%

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

2022

View full text Add to dashboard Cite

The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.

show abstract

Genetics, pathogenesis and therapeutic developments for Usher syndrome type 2

Cited by 21 publications

References 194 publications

Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1

Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1

Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Contact Info

Product

Resources

About