Affinage

USH2A

Usherin · UniProt O75445

Length
5202 aa
Mass
575.6 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USH2A encodes usherin, a large transmembrane extracellular matrix protein whose long isoform carries a Laminin N-terminal domain, multiple laminin EGF-like (LE) and fibronectin type III (FN3) repeats, a transmembrane segment, and a C-terminal PDZ-binding motif, and is required for both cochlear and retinal function (PMID:10775529, PMID:10909849, PMID:15015129). Through its PDZ-binding tail, usherin directly assembles with the PDZ scaffold whirlin and the adhesion GPCR VLGR1/ADGRV1 into a macromolecular complex that localizes to the periciliary membrane/connecting cilium of photoreceptors and the ankle-link complex of cochlear hair cell stereocilia (PMID:16434480, PMID:26401052). This complex is obligatory: loss of any single component mislocalizes and destabilizes all three, and re-supplying whirlin alone is sufficient to recruit and stabilize usherin and VLGR1 at the periciliary membrane, establishing whirlin as the organizing scaffold (PMID:20502675, PMID:21212183). The complex is further integrated with USH1 proteins—usherin binds the SANS scaffold to form a ternary SANS/usherin/whirlin assembly, and myosin VIIa is required for USH2 complex assembly at cochlear ankle links but not in photoreceptors, defining tissue-specific anchoring (PMID:28137943, PMID:28031293). Complex abundance is post-translationally controlled: ADGRV1-driven local cAMP-PKA signaling inhibits whirlin phosphorylation, and phosphorylated whirlin recruits the E3 ligase WDSUB1 to ubiquitinate and destabilize usherin (PMID:37066759). Loss of usherin disorganizes stereocilia and disrupts retinal basement-membrane fibronectin assembly and cell adhesion, producing progressive photoreceptor degeneration (PMID:26401052, PMID:30242501), and usherin is additionally expressed in terminal Schwann cells of Meissner's corpuscles where it is required for vibrotactile mechanosensitivity (PMID:33288907). Disease-causing lesions act through truncation, missense changes in critical ECM domains such as the fifth LE domain, and aberrant splicing including deep-intronic pseudoexon insertion, several of which are correctable by antisense-oligonucleotide-mediated exon or pseudoexon skipping (PMID:10775529, PMID:10909849, PMID:22009552, PMID:27802265, PMID:33895329).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    Established that USH2A encodes an ECM/basal-lamina-type protein and that specific structural domains are functionally essential, anchoring the protein's molecular identity.

    Evidence DNA sequencing, domain analysis, and disease-mutation mapping identifying LE and FN3 repeats with pathogenic missense in the fifth LE domain

    PMID:10775529 PMID:10909849

    Open questions at the time
    • Did not define a binding partner or in vivo complex
    • No demonstration of how LE-domain mutations alter protein behavior
  2. 2002 Medium

    Localized USH2A expression to photoreceptors of the retina and to the cochlea, identifying the cell types whose dysfunction underlies the syndrome.

    Evidence In situ hybridization across rat, mouse, and human retinal sections plus radiation hybrid/FISH mapping

    PMID:12160733

    Open questions at the time
    • mRNA localization without functional consequence shown
    • No protein-level subcellular localization
  3. 2004 Medium

    Defined the disease-relevant long isoform (isoform b) as a 5,202-aa transmembrane protein with an intracellular PDZ-binding motif, explaining why both hearing and vision require this isoform.

    Evidence cDNA cloning of novel exons 22-73, expression profiling, and patient mutation analysis

    PMID:15015129

    Open questions at the time
    • Function of the PDZ-binding motif not yet tested
    • No interacting scaffold identified at this stage
  4. 2006 High

    Showed usherin directly binds whirlin and VLGR1b and co-localizes with them at photoreceptor and hair cell ciliary/synaptic regions, converting the protein from an isolated ECM molecule into a defined scaffold complex member.

    Evidence Pull-down/co-IP interaction assays plus immunohistochemical co-localization in retina and cochlea

    PMID:16434480

    Open questions at the time
    • In vitro binding did not establish in vivo dependency
    • Stoichiometry and complex architecture undefined
  5. 2010 High

    Demonstrated the three USH2 proteins form an obligatory complex in vivo where loss of any one mislocalizes and destabilizes the others, establishing mutual interdependence and explaining genotype–phenotype distinctions tied to whirlin PDZ domains.

    Evidence Targeted gene knockout mice with immunofluorescence, Western blot, ERG, and histology

    PMID:20502675

    Open questions at the time
    • Mechanism stabilizing each protein not defined
    • Did not identify which component nucleates assembly
  6. 2011 High

    Identified whirlin as the sufficient organizer of the complex by showing transgenic whirlin restores USH2A and VLGR1 localization in whirlin-null photoreceptors.

    Evidence AAV2/5 subretinal whirlin rescue in knockout mice with immunofluorescence, immuno-EM, Western blot, and ERG

    PMID:21212183

    Open questions at the time
    • Did not address whether usherin reciprocally stabilizes whirlin
    • Cochlear sufficiency not tested in this experiment
  7. 2011 High

    Established splicing as a distinct disease mechanism for USH2A, showing both the common c.2299delG and deep-intronic and canonical splice-site variants disrupt normal mRNA processing, including pseudoexon (PE40) inclusion.

    Evidence Patient nasal-cell RT-PCR, hybrid minigene splice assays, and bioinformatic splice prediction across multiple variants

    PMID:20497194 PMID:22009552 PMID:24607488

    Open questions at the time
    • Did not establish protein-level consequences in target tissues
    • Quantitative impact on usherin abundance not measured
  8. 2015 High

    Resolved the cochlear architecture by placing USH2 proteins in the stereociliary ankle-link complex with distinct, non-equivalent roles, defining ADGRV1 as most critical and usherin's contribution to hair cell growth and rigidity.

    Evidence Immunofluorescence across multiple USH2 mutant mouse lines with stereociliary morphology and auditory testing

    PMID:26401052

    Open questions at the time
    • Did not define molecular hierarchy of assembly
    • Link between ankle-link disruption and signaling not addressed
  9. 2017 High

    Integrated USH2A into the broader Usher network by showing usherin binds the USH1 scaffold SANS to form a ternary complex and that myosin VIIa is required for USH2 assembly in cochlea but not photoreceptors, revealing tissue-specific anchoring logic.

    Evidence Co-IP/pull-down, proximity ligation assay, immunohistochemistry in rodent and human retina, and USH1 mutant mouse models

    PMID:28031293 PMID:28137943

    Open questions at the time
    • Mechanism of myosin VIIa-dependent transport vs anchoring not separated
    • Functional consequence of the SANS/usherin/whirlin complex in vivo not isolated
  10. 2018 High

    Used a zebrafish knockout to define downstream pathology, implicating disrupted retinal basement-membrane fibronectin assembly and weakened cell adhesion as mechanisms driving progressive photoreceptor degeneration.

    Evidence TALEN knockout zebrafish with ABR, ERG, histology, and fibronectin immunohistochemistry

    PMID:30242501

    Open questions at the time
    • Causal link between fibronectin defect and photoreceptor death not dissected
    • Did not test whether adhesion defect is cell-autonomous
  11. 2020 High

    Extended USH2A function beyond the ear and eye, showing it acts in Meissner's corpuscle terminal Schwann cells to support vibrotactile mechanosensitivity in mice and patients.

    Evidence Immunohistochemistry plus mechanoreceptor electrophysiology in Ush2a-/- mice and psychophysical vibrotactile testing in patients

    PMID:33288907

    Open questions at the time
    • Molecular role of usherin within Schwann cells not defined
    • Whether the USH2 scaffold operates in this tissue unknown
  12. 2023 High

    Defined a post-translational control circuit: ADGRV1 cAMP-PKA signaling inhibits whirlin phosphorylation, and phospho-whirlin recruits the E3 ligase WDSUB1 to ubiquitinate and destabilize usherin, explaining how complex integrity governs USH2A protein levels.

    Evidence Adgrv1 knockin mice, yeast two-hybrid, FlAsH-BRET, NMR, mutagenesis, and ubiquitination co-IP

    PMID:37066759

    Open questions at the time
    • Relevance of this circuit in photoreceptors vs cochlea not fully delineated
    • Other substrates of WDSUB1 in the complex not explored
  13. 2023 Medium

    Showed full-length usherin replacement is feasible, with non-viral S/MAR vectors carrying the 15.6-kb coding sequence restoring USH2 complex localization, addressing the gene-size barrier to therapy.

    Evidence S/MAR vector transfection in patient fibroblasts and microinjection in ush2a zebrafish with complex-localization readout

    PMID:37337429

    Open questions at the time
    • Single lab, two model systems
    • Durable functional rescue in mammalian retina not demonstrated
  14. 2025 High

    Demonstrated precise correction of a point mutation in vivo, with split-intein AAV9 base editing restoring USH2A protein expression in a humanized knockin mouse.

    Evidence Humanized c.11864G>A knockin mouse with split-intein AAV9 base editor, NGS editing quantification, and protein restoration assays

    PMID:39881543

    Open questions at the time
    • Bystander edits present at ~13%
    • Long-term functional rescue of vision/hearing not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How usherin's extracellular LE/FN3 domains mechanically couple to the ECM and stereociliary/ciliary architecture, and how this links to its intracellular scaffold and degradation control across distinct tissues, remains incompletely resolved.
  • No structural model of usherin in the assembled complex
  • Force-transmission role of LE/FN3 domains not directly measured
  • Whether the cAMP-PKA-WDSUB1 axis operates identically in photoreceptors, hair cells, and Schwann cells is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060089 molecular transducer activity 1 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005929 cilium 3 GO:0005576 extracellular region 2 GO:0031012 extracellular matrix 2
Pathway
R-HSA-9709957 Sensory Perception 3 R-HSA-1474244 Extracellular matrix organization 1 R-HSA-162582 Signal Transduction 1
Partners
ADGRV1MYO7APDZD7USH1GWDSUB1WHRN
Complex memberships
SANS/usherin/whirlin ternary USH1/USH2 complexUSH2 ankle-link complex (usherin/ADGRV1/whirlin/PDZD7)periciliary membrane complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 USH2A encodes a protein (usherin) with laminin EGF-like (LE) domains and fibronectin type III (FN3) repeats, characteristic of extracellular matrix/basal lamina proteins; missense mutations in the fifth LE domain (e.g., Cys759Phe) cause disease, indicating these domains are functionally critical. DNA sequencing with domain analysis and mutation mapping American journal of human genetics Medium 10775529 10909849
2004 The long isoform of USH2A (isoform b) encodes a 5,202-amino-acid transmembrane protein with a large extracellular domain containing a Laminin N-terminal domain, multiple LE and FN3 repeats, a transmembrane region, and an intracellular PDZ-binding motif at the C-terminus; pathogenic mutations in the novel exons 22–73 cause both hearing and vision loss, indicating this long isoform is required for both cochlear and retinal function. Identification of novel exons by cDNA cloning/sequencing; semiquantitative expression profiling; mutation analysis in patients American journal of human genetics Medium 15015129
2006 USH2A isoform b directly associates with the PDZ scaffold protein whirlin (DFNB31/USH2D) and with VLGR1b; these three proteins co-localize at the synaptic regions and at the connecting cilium/periciliary membrane of photoreceptor cells and outer hair cells, forming a macromolecular PDZ protein scaffold. Direct protein-protein interaction assays (pull-down/co-IP), co-localization by immunohistochemistry in retina and cochlea Human molecular genetics High 16434480
2010 The three USH2 proteins (usherin/USH2A, VLGR1, and whirlin) form an obligatory functional complex at the periciliary membrane complex (PMC) in mouse photoreceptors; loss of any single USH2 protein disrupts the normal localization of all three and causes protein destabilization. The whirlin long isoform's N-terminal PDZ domains mediate formation of this multi-protein complex; ablation of these domains causes Usher syndrome (retinal + inner ear defects), whereas sparing them results in non-syndromic hearing loss only. Targeted gene disruption in mice (knockout), immunofluorescence localization, Western blot, electroretinography, histology PLoS genetics High 20502675
2011 AAV-mediated delivery of whirlin transgene to whirlin-knockout photoreceptors restores correct localization and expression of both USH2A and VLGR1 at the periciliary membrane complex, demonstrating that whirlin is sufficient to recruit and stabilize the USH2 protein complex in photoreceptors. AAV2/5 subretinal injection rescue experiment in knockout mice; immunofluorescence, immunoelectron microscopy, Western blot, ERG Investigative ophthalmology & visual science High 21212183
2002 USH2A mRNA is expressed in the outer nuclear layer of the adult retina (photoreceptors) and in the cochlea in rat, mouse, and human; in developing rat retina, Ush2a mRNA appears in the neuroepithelium at embryonic day 17, identifying photoreceptors as the primary cellular source of USH2A in the retina. In situ hybridization in rat, mouse, and human retinal sections; radiation hybrid mapping; fluorescence in situ hybridization Genomics Medium 12160733
2015 In the cochlea, USH2 proteins (USH2A, ADGRV1/GPR98, whirlin, PDZD7) assemble into the ankle link complex (ALC) at the stereociliary bundle. USH2 proteins play different roles in ALC assembly, with ADGRV1 being the most critical. Loss of individual USH2 proteins causes variable stereociliary morphological defects correlating with severity of ALC disruption; USH2A loss affects inner hair cell stereociliary growth and outer hair cell stereociliary rigidity. Immunofluorescence in multiple USH2 mutant mouse lines; stereociliary morphology analysis; auditory functional testing Human molecular genetics High 26401052
2017 USH2A (usherin) directly interacts with the USH1G scaffold protein SANS, and together with whirlin they form a ternary USH1/USH2 complex. This complex localizes to the periciliary region, inner segment, and synapses of rodent and human photoreceptor cells. Pathogenic mutations in USH1G (SANS) severely impair formation of this SANS/usherin/whirlin complex. Protein-protein interaction assays (co-IP/pull-down), proximity ligation assay, immunohistochemistry in rodent and human retina, co-expression studies Human molecular genetics High 28137943
2017 In cochlear hair cells, myosin VIIa (USH1B) is required for USH2 complex assembly at ankle links, indicating a transport and/or anchoring role for myosin VIIa for USH2 proteins; however, myosin VIIa is not required for USH2 complex assembly in photoreceptors. PDZD7 and whirlin function synergistically in cochlear USH2 complex assembly. A novel interaction between myosin VIIa and PDZD7 was identified. FLAG pull-down assay for novel interaction; USH1 mutant mouse models with immunofluorescence to assess USH2 complex integrity Human molecular genetics High 28031293
2020 USH2A protein is expressed in terminal Schwann cells within Meissner's corpuscles in fingertip skin (not in sensory neurons themselves). Loss of USH2A in corpuscular end-organs reduces mechanoreceptor sensitivity to vibration and impairs vibrotactile perception in both Ush2a-/- mice and USH2A patients with biallelic pathogenic mutations. Immunohistochemistry for USH2A protein localization; electrophysiological recording of rapidly adapting mechanoreceptors in Ush2a-/- mice; psychophysical vibrotactile testing in patients Nature neuroscience High 33288907
2018 Knockout of ush2a in zebrafish causes early-onset auditory disorder with abnormal inner ear stereocilia morphology and late-onset progressive rod-then-cone photoreceptor degeneration. Disruption of fibronectin assembly at the retinal basement membrane and weakened cell adhesion were identified as pathogenic mechanisms. Expression of Ush1b and Ush1c was upregulated in ush2a-null zebrafish. TALEN-based knockout zebrafish; ABR auditory testing; ERG; histology; immunohistochemistry for fibronectin assembly Human genetics High 30242501
2011 The common c.2299delG mutation in USH2A exon 13 affects RNA splicing in addition to creating a frameshift; nasal cell RT-PCR from homozygous patients showed significantly reduced amplification of the expected product compared to controls, consistent with disruption of an exonic splicing enhancer and/or creation of an exonic splicing silencer. RT-PCR from nasal epithelial cells of homozygous c.2299delG patients vs. controls; bioinformatics splice site analysis Experimental eye research Medium 24607488
2011 A deep-intronic mutation in USH2A (c.7595-2144A>G) creates a high-quality splice donor site that causes insertion of a pseudoexon (PE40) into the mature transcript, predicted to result in premature termination of usherin translation; this was confirmed by RNA analysis of nasal cells and minigene assay. RNA analysis of nasal epithelial cells; minigene splice assay Human mutation High 22009552
2016 Antisense oligonucleotides (AONs) targeting the PE40 splice acceptor site and exonic splice enhancer regions of USH2A pre-mRNA caused significant splice correction in patient-derived fibroblasts and in a minigene assay for the c.7595-2144A>G deep-intronic mutation, demonstrating that aberrant pseudoexon inclusion caused by this mutation can be therapeutically corrected at the RNA level. AON treatment of patient fibroblasts; minigene splice assay; RT-PCR to measure splice correction Molecular therapy. Nucleic acids High 27802265
2021 Morpholino-induced skipping of ush2a exon 13 in zebrafish ush2a mutants produces a shortened usherinΔexon13 protein and completely restores retinal function; antisense oligonucleotide QR-421a induces concentration-dependent USH2A exon 13 skipping in iPSC-derived photoreceptor precursors from a c.2299delG USH patient. Mouse surrogate mQR-421a reaches the retinal outer nuclear layer after intravitreal injection and maintains exon-skipping for at least 6 months. Morpholino exon skipping in zebrafish with ERG functional rescue; AON treatment of iPSC-derived photoreceptors; intravitreal injection in mice with long-term RT-PCR monitoring Molecular therapy : the journal of the American Society of Gene Therapy High 33895329
2019 CRISPR/Cas9-mediated deletion of mouse Ush2a exon 12 (equivalent to human exon 13) produces a shortened Ush2a-ΔEx12 protein that localizes correctly in the cochlea; when expressed on an Ush2a-null background, it restores impaired hair cell structure and auditory function, demonstrating that a shortened usherin lacking this exon is functional. CRISPR/Cas9 exon deletion in mice; immunohistochemistry for protein localization; auditory brainstem response for functional rescue Advances in experimental medicine and biology High 31884594
2023 ADGRV1 regulates USH2A protein stability through local cAMP-PKA signaling that inhibits WHRN (whirlin) phosphorylation; phosphorylated WHRN recruits the E3 ligase WDSUB1, which ubiquitinates USH2A and destabilizes it. Loss-of-function ADGRV1 mutation (Y6236fsX1) disrupts this signaling, leading to USH2A instability and stereocilia disorganization. Adgrv1 Y6236fsX1 knockin mice; yeast two-hybrid screening for WDSUB1; FlAsH-BRET assay; NMR spectrometry; mutagenesis; co-IP for ubiquitination; immunofluorescence for ALC integrity Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 37066759
2023 Non-viral S/MAR episomal plasmid vectors carrying the full-length 15.6-kb USH2A coding sequence drive persistent usherin expression in patient-derived fibroblasts and restore Usher 2 complex localization in photoreceptors of ush2au507 zebrafish retinas, demonstrating that full-length functional usherin can rescue the USH2 complex. S/MAR vector transfection in patient fibroblasts (Western blot for usherin); microinjection in ush2a zebrafish with 12-month GFP tracking and immunohistochemistry for USH2 complex rescue Molecular therapy : the journal of the American Society of Gene Therapy Medium 37337429
2023 CRISPR/Cas9-generated zebrafish mutants lacking ush2a exons orthologous to human exons 30–31 or 39–40 show usherin loss and photopigment mislocalization; dual exon skipping using antisense oligonucleotides in vitro restores the reading frame and rescues usherin expression and photopigment localization in the retina, validating a protein domain-oriented dual-exon-skipping therapeutic strategy. CRISPR/Cas9 zebrafish genomic deletion; ASO-induced exon skipping in vitro; immunohistochemistry for usherin and photopigment localization Molecular therapy. Nucleic acids High 37313440
2011 Five putative splice-site variants in USH2A (c.1841-2A>G, c.2167+5G>A, c.5298+1G>C) were confirmed to abolish consensus splice sites, causing exon skipping; the c.2167+5G>A variant additionally activated a cryptic donor splice site. These molecular consequences were demonstrated using hybrid minigene assays. Hybrid minigene splice assay; bioinformatics splice-site prediction Clinical genetics Medium 20497194
2019 USH2A mutations in iPSC-derived retinal organoids cause reduced laminin expression, abnormal retinal neuroepithelium differentiation and polarization, defective retinal progenitor cell development, and lower expression of cilium-associated genes (CFAP43, PIFO) and dopaminergic synapse-related genes; RPE cells from these organoids show abnormal morphology and reduced expression of MITF, PEDF, and RPE65. iPSC-derived retinal organoids from USH2A patient; immunofluorescence; transcriptomics; comparison with isogenic controls Frontiers in cellular neuroscience Medium 31481876
2025 Split-intein AAV9 delivery of adenine base editor components to a humanized Ush2a c.11864G>A knockin mouse restored USH2A protein expression with a correction rate of 65% ± 3% at the mutant base pair (52% ± 3% excluding bystander amino acid changes), demonstrating in vivo therapeutic base editing of USH2A. Humanized knockin mouse model; split-intein AAV9 delivery; next-generation sequencing for editing efficiency; Western blot/immunohistochemistry for protein restoration Molecular therapy : the journal of the American Society of Gene Therapy High 39881543

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. American journal of human genetics 219 10775529
2004 Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II. American journal of human genetics 169 15015129
2006 The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Human molecular genetics 157 16434480
2010 Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. Journal of medical genetics 143 20507924
2021 Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Molecular therapy : the journal of the American Society of Gene Therapy 124 33895329
2016 Antisense Oligonucleotide-based Splice Correction for USH2A-associated Retinal Degeneration Caused by a Frequent Deep-intronic Mutation. Molecular therapy. Nucleic acids 118 27802265
2010 Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PLoS genetics 118 20502675
2015 A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. European journal of human genetics : EJHG 108 25649381
2004 Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Experimental eye research 100 15325563
2011 Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. Human mutation 96 22009552
2008 Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Human molecular genetics 95 18463160
2008 Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Human mutation 91 18273898
2008 Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene. Investigative ophthalmology & visual science 88 18641288
2020 USH2A-retinopathy: From genetics to therapeutics. Experimental eye research 84 33121974
2015 Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations. Human mutation 75 26629787
2000 Identification of novel USH2A mutations: implications for the structure of USH2A protein. European journal of human genetics : EJHG 74 10909849
2019 Modeling Retinitis Pigmentosa: Retinal Organoids Generated From the iPSCs of a Patient With the USH2A Mutation Show Early Developmental Abnormalities. Frontiers in cellular neuroscience 70 31481876
2001 A common ancestral origin of the frequent and widespread 2299delG USH2A mutation. American journal of human genetics 69 11402400
2006 Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. Journal of medical genetics 68 17085681
2014 Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. Human mutation 62 24944099
2015 Clinical aspects of Usher syndrome and the USH2A gene in a cohort of 433 patients. JAMA ophthalmology 57 25375654
2011 Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Investigative ophthalmology & visual science 57 21212183
2017 USH2A Gene Editing Using the CRISPR System. Molecular therapy. Nucleic acids 55 28918053
2013 Targeted exome sequencing identified novel USH2A mutations in Usher syndrome families. PloS one 55 23737954
2002 Paternal uniparental heterodisomy with partial isodisomy of chromosome 1 in a patient with retinitis pigmentosa without hearing loss and a missense mutation in the Usher syndrome type II gene USH2A. Archives of ophthalmology (Chicago, Ill. : 1960) 55 12427073
2012 Non-USH2A mutations in USH2 patients. Human mutation 54 22147658
2020 USH2A is a Meissner's corpuscle protein necessary for normal vibration sensing in mice and humans. Nature neuroscience 52 33288907
2011 Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations. Orphanet journal of rare diseases 52 22004887
2005 Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. Investigative ophthalmology & visual science 51 15671307
2004 Genetic analysis of 2299delG and C759F mutations (USH2A) in patients with visual and/or auditory impairments. European journal of human genetics : EJHG 51 14970843
2010 The USH2A c.2299delG mutation: dating its common origin in a Southern European population. European journal of human genetics : EJHG 48 20145675
2017 Characterization of the ternary Usher syndrome SANS/ush2a/whirlin protein complex. Human molecular genetics 47 28137943
2013 Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. Orphanet journal of rare diseases 47 23924366
2002 Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively. Human mutation 47 12112664
2016 A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa. Hearing research 46 27318125
2018 Knockout of ush2a gene in zebrafish causes hearing impairment and late onset rod-cone dystrophy. Human genetics 43 30242501
2004 USH2A mutation analysis in 70 Dutch families with Usher syndrome type II. Human mutation 43 15241801
2001 Spectrum of mutations in USH2A in British patients with Usher syndrome type II. Experimental eye research 43 11311042
2017 The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells. Human molecular genetics 38 28031293
2015 Individual USH2 proteins make distinct contributions to the ankle link complex during development of the mouse cochlear stereociliary bundle. Human molecular genetics 38 26401052
2019 Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation. Clinical and experimental otorhinolaryngology 37 31674169
2011 Seven novel mutations in the long isoform of the USH2A gene in Chinese families with nonsyndromic retinitis pigmentosa and Usher syndrome Type II. Molecular vision 37 21686329
2009 Identification of 11 novel mutations in USH2A among Japanese patients with Usher syndrome type 2. Clinical genetics 37 19737284
2020 USH2A variants in Chinese patients with Usher syndrome type II and non-syndromic retinitis pigmentosa. The British journal of ophthalmology 32 32675063
2011 Audiological findings in 100 USH2 patients. Clinical genetics 32 21895633
2009 Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II. Journal of human genetics 32 19881469
2020 Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease. The British journal of ophthalmology 31 32188678
2008 Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type II. Molecular vision 31 19023448
2000 Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 families. Human mutation 31 10738000
2007 Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2. Archives of ophthalmology (Chicago, Ill. : 1960) 29 17296898
2017 Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients. Scientific reports 28 28894305
2014 Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis. PloS one 28 25133613
2003 Pure tone hearing thresholds and speech recognition scores in Dutch patients carrying mutations in the USH2A gene. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 28 12544030
2019 In Vivo Assessment of Potential Therapeutic Approaches for USH2A-Associated Diseases. Advances in experimental medicine and biology 27 31884594
2009 Cell transplantation to arrest early changes in an ush2a animal model. Investigative ophthalmology & visual science 27 19959642
2008 Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. Genetic testing 27 18452394
2008 An USH2A founder mutation is the major cause of Usher syndrome type 2 in Canadians of French origin and confirms common roots of Quebecois and Acadians. European journal of human genetics : EJHG 27 18665195
2022 Retinal organoids and microfluidic chip-based approaches to explore the retinitis pigmentosa with USH2A mutations. Frontiers in bioengineering and biotechnology 25 36185441
2018 Poor Splice-Site Recognition in a Humanized Zebrafish Knockin Model for the Recurrent Deep-Intronic c.7595-2144A>G Mutation in USH2A. Zebrafish 25 30281416
2021 Generation and Genetic Correction of USH2A c.2299delG Mutation in Patient-Derived Induced Pluripotent Stem Cells. Genes 24 34070435
2018 Searching the second hit in patients with inherited retinal dystrophies and monoallelic variants in ABCA4, USH2A and CEP290 by whole-gene targeted sequencing. Scientific reports 24 30190494
1996 The construction of a yeast artificial chromosome (YAC) contig in the vicinity of the Usher syndrome type IIa (USH2A) gene in 1q41. Genomics 24 8661107
2023 USH2A variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids. HGG advances 23 37654703
2014 The effect of the common c.2299delG mutation in USH2A on RNA splicing. Experimental eye research 23 24607488
2014 MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome. Molecular vision 23 25558175
2000 [Molecular genetics of pigmentary retinopathies: identification of mutations in CHM, RDS, RHO, RPE65, USH2A and XLRS1 genes]. Journal francais d'ophtalmologie 22 11139690
2018 Efficacy Outcome Measures for Clinical Trials of USH2A Caused by the Common c.2299delG Mutation. American journal of ophthalmology 21 29953849
2011 Novel USH2A mutations in Japanese Usher syndrome type 2 patients: marked differences in the mutation spectrum between the Japanese and other populations. Journal of human genetics 20 21593743
2016 Immunogenicity and protective efficacy of Brucella abortus recombinant protein cocktail (rOmp19+rP39) against B. abortus 544 and B. melitensis 16M infection in murine model. Molecular immunology 18 26826463
2015 Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F. American journal of medical genetics. Part A 18 25823529
2013 Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa. Molecular vision 18 24227914
2009 Audiometric characteristics of USH2a patients. Audiology & neuro-otology 18 19129697
2022 The RUSH2A Study: Dark-Adapted Visual Fields in Patients With Retinal Degeneration Associated With Biallelic Variants in the USH2A Gene. Investigative ophthalmology & visual science 17 35293952
2022 Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy. Frontiers in aging neuroscience 17 36034145
2020 Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients. International journal of molecular sciences 17 33105608
2020 Correlation between Genotype and Phenotype in 69 Chinese Patients with USH2A Mutations: A comparative study of the patients with Usher Syndrome and Nonsyndromic Retinitis Pigmentosa. Acta ophthalmologica 17 33124170
2019 Whole exome sequencing identifies novel USH2A mutations and confirms Usher syndrome 2 diagnosis in Chinese retinitis pigmentosa patients. Scientific reports 17 30948794
2002 Identification of the mouse and rat orthologs of the gene mutated in Usher syndrome type IIA and the cellular source of USH2A mRNA in retina, a target tissue of the disease. Genomics 17 12160733
2023 A protein domain-oriented approach to expand the opportunities of therapeutic exon skipping for USH2A-associated retinitis pigmentosa. Molecular therapy. Nucleic acids 16 37313440
2023 Successful large gene augmentation of USH2A with non-viral episomal vectors. Molecular therapy : the journal of the American Society of Gene Therapy 16 37337429
2021 USH2A Mutation is Associated With Tumor Mutation Burden and Antitumor Immunity in Patients With Colon Adenocarcinoma. Frontiers in genetics 16 34795697
2018 Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families. PloS one 16 29912909
2020 Establishing Genotype-phenotype Correlation in USH2A-related Disorders to Personalize Audiological Surveillance and Rehabilitation. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 15 32176120
2020 A case of Usher syndrome type IIA caused by a rare USH2A homozygous frameshift variant with maternal uniparental disomy (UPD) in a Chinese family. Journal of cellular and molecular medicine 15 32449591
2019 Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation. Genes 15 31817543
2018 Mutation screening of the USH2A gene in retinitis pigmentosa and USHER patients in a Han Chinese population. Eye (London, England) 15 29899460
2014 Novel deletions involving the USH2A gene in patients with Usher syndrome and retinitis pigmentosa. Molecular vision 15 25352746
2023 Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 37066759
2011 Functional analysis of splicing mutations in MYO7A and USH2A genes. Clinical genetics 14 20497194
1998 The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region. Human genetics 14 9760205
2023 USH2A Gene Mutations in Rabbits Lead to Progressive Retinal Degeneration and Hearing Loss. Translational vision science & technology 13 36795064
2021 Spectral-Domain Optical Coherence Tomography Analysis in Syndromic and Nonsyndromic Forms of Retinitis Pigmentosa due to USH2A Genetic Variants. Ophthalmic research 13 34781295
2021 The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A. International journal of molecular sciences 13 34948090
2014 The first USH2A mutation analysis of Japanese autosomal recessive retinitis pigmentosa patients: a totally different mutation profile with the lack of frequent mutations found in Caucasian patients. Journal of human genetics 13 25078356
2022 Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome. Frontiers in genetics 12 36110214
2019 Double Hyperautofluorescent Rings in Patients with USH2A-Retinopathy. Genes 12 31766479
2010 Novel USH2A compound heterozygous mutations cause RP/USH2 in a Chinese family. Molecular vision 12 20309401
2000 Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2). Ophthalmic genetics 12 10916187
2025 Systematic empirical evaluation of individual base editing targets: Validating therapeutic targets in USH2A and comparison of methods. Molecular therapy : the journal of the American Society of Gene Therapy 11 39881543
2019 Novel USH1G homozygous variant underlying USH2-like phenotype of Usher syndrome. European journal of ophthalmology 11 31566003

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