usher syndromes


Summary: Autosomal recessive hereditary disorders characterized by congenital SENSORINEURAL HEARING LOSS and RETINITIS PIGMENTOSA. Genetically and symptomatically heterogeneous, clinical classes include type I, type II, and type III. Their severity, age of onset of retinitis pigmentosa and the degree of vestibular dysfunction are variable.

Top Publications

  1. Roux A, Faugère V, Vache C, Baux D, Besnard T, Léonard S, et al. Four-year follow-up of diagnostic service in USH1 patients. Invest Ophthalmol Vis Sci. 2011;52:4063-71 pubmed publisher
    ..Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases. ..
  2. McGee T, Seyedahmadi B, Sweeney M, Dryja T, Berson E. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet. 2010;47:499-506 pubmed publisher
  3. Vastinsalo H, Jalkanen R, Dinculescu A, Isosomppi J, Geller S, Flannery J, et al. Alternative splice variants of the USH3A gene Clarin 1 (CLRN1). Eur J Hum Genet. 2011;19:30-5 pubmed publisher
    ..The complexity of the CLRN1 gene and the identification of multiple splice variants may partially explain why mutations in CLRN1 result in substantial variation in clinical phenotype. ..
  4. Aller E, Jaijo T, Beneyto M, Najera C, Morera C, Perez Garrigues H, et al. Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome. Ophthalmic Genet. 2007;28:151-5 pubmed
    ..Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, one can conclude that USH1G has a minor involvement in Usher syndrome pathogenesis. ..
  5. Lentz J, Pan F, Ng S, Deininger P, Keats B. Ush1c216A knock-in mouse survives Katrina. Mutat Res. 2007;616:139-44 pubmed
    ..RT-PCR analysis of the cochlea and retina from 216AA mice shows the same 35 base deletion characteristic of Usher IC patients. ..
  6. Pan L, Yan J, Wu L, Zhang M. Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23. Proc Natl Acad Sci U S A. 2009;106:5575-80 pubmed publisher
    ..The multidentate binding mode between harmonin and cadherin 23 provides a structural and biochemical basis for the harmonin-mediated assembly of stable tip link complex in the auditory hair cells. ..
  7. Ebermann I, Wilke R, Lauhoff T, Lübben D, Zrenner E, Bolz H. Two truncating USH3A mutations, including one novel, in a German family with Usher syndrome. Mol Vis. 2007;13:1539-47 pubmed
    ..This is the first description of a German family with USH due to USH3A mutations, including one novel. Our findings indicate that also in the Central European population, USH3A mutations should be considered in cases of USH. ..
  8. Yan J, Pan L, Chen X, Wu L, Zhang M. The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins. Proc Natl Acad Sci U S A. 2010;107:4040-5 pubmed publisher
    ..Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins. ..
  9. Le Guédard S, Faugère V, Malcolm S, Claustres M, Roux A. Large genomic rearrangements within the PCDH15 gene are a significant cause of USH1F syndrome. Mol Vis. 2007;13:102-7 pubmed
    ..The intron sizes of PCDH15 are up to 150 kb, and the first three exons of the gene cover 0.42 Mb. The genomic structure of any gene should be taken into consideration when designing a mutation screening strategy. ..

More Information


  1. Kremer H, Van Wijk E, Märker T, Wolfrum U, Roepman R. Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet. 2006;15 Spec No 2:R262-70 pubmed
    ..A third link can be established to the integrin transmembrane signaling network. The Usher interactome, as outlined in this review, participates in pathways common in inner ear and retina that are disrupted in the Usher syndrome. ..
  2. Wu C, Chiu C. Usher syndrome with psychotic symptoms: two cases in the same family. Psychiatry Clin Neurosci. 2006;60:626-8 pubmed
    ..Furthermore, the authors compare their psychiatric symptoms with other reports and the possible etiologies of psychotic symptoms are discussed. ..
  3. Vache C, Besnard T, le Berre P, García García G, Baux D, Larrieu L, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. Hum Mutat. 2012;33:104-8 pubmed publisher
    ..Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs). ..
  4. Plantinga R, Pennings R, Huygen P, Sankila E, Tuppurainen K, Kleemola L, et al. Visual impairment in Finnish Usher syndrome type III. Acta Ophthalmol Scand. 2006;84:36-41 pubmed
    ..At a given age, visual field impairment in USH3 patients was similar to that in USH1b patients but poorer than in USH2a patients. ..
  5. Malm E, Ponjavic V, Moller C, Kimberling W, Andreasson S. Phenotypes in defined genotypes including siblings with Usher syndrome. Ophthalmic Genet. 2011;32:65-74 pubmed publisher
    ..Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome. ..
  6. Malm E, Ponjavic V, Moller C, Kimberling W, Stone E, Andreasson S. Alteration of rod and cone function in children with Usher syndrome. Eur J Ophthalmol. 2011;21:30-8 pubmed
    ..To evaluate the retinal function, with emphasis on phenotype and rate of progression, in infants and children with different genotypes of Usher syndrome...
  7. Jaijo T, Aller E, Oltra S, Beneyto M, Najera C, Ayuso C, et al. Mutation profile of the MYO7A gene in Spanish patients with Usher syndrome type I. Hum Mutat. 2006;27:290-1 pubmed
    ..Based on our results we can conclude there is an absence of hot spot mutations in the MYO7A gene and that this gene plays a major role in Usher syndrome. ..
  8. Ebermann I, Lopez I, Bitner Glindzicz M, Brown C, Koenekoop R, Bolz H. Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population. Genome Biol. 2007;8:R47 pubmed
    ..Our results, however, show that carriers of the c.216G>A allele haplotype belonged to the early founders of both the Acadian and the Quebec population. ..
  9. Baux D, Larrieu L, Blanchet C, Hamel C, Ben Salah S, Vielle A, et al. Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients. Hum Mutat. 2007;28:781-9 pubmed
    ..We have identified a previously unrecognized cysteine rich structural domain, containing 12 dicysteine repeats, and show that three missense mutations result in the loss of one of a pair of the defining cysteine-cysteine pairs. ..
  10. Akoury E, El Zir E, Mansour A, Megarbane A, Majewski J, Slim R. A novel 5-bp deletion in Clarin 1 in a family with Usher syndrome. Ophthalmic Genet. 2011;32:245-9 pubmed publisher
    ..Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III. ..
  11. Vozzi D, Aaspõllu A, Athanasakis E, Berto A, Fabretto A, Licastro D, et al. Molecular epidemiology of Usher syndrome in Italy. Mol Vis. 2011;17:1662-8 pubmed
  12. Bonnet C, Grati M, Marlin S, Levilliers J, Hardelin J, Parodi M, et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis. 2011;6:21 pubmed publisher
    ..Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy. ..
  13. Aller E, Jaijo T, Beneyto M, Najera C, Oltra S, Ayuso C, et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006;43:e55 pubmed
    ..On analysing the new 52 exons, fourteen novel mutations were identified in 14 out of the 32 cases studied, including 7 missense, 5 frameshift, 1 duplication and a putative splice-site mutation. ..
  14. Williams D. Usher syndrome: animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res. 2008;48:433-41 pubmed
    ..Progress in this treatment approach has been achieved by correction of mutant phenotypes in Myo7a-null mouse retinas, following lentiviral delivery of MYO7A. ..
  15. Gerber S, Bonneau D, Gilbert B, Munnich A, Dufier J, Rozet J, et al. USH1A: chronicle of a slow death. Am J Hum Genet. 2006;78:357-9 pubmed
  16. Bahloul A, Michel V, Hardelin J, Nouaille S, Hoos S, Houdusse A, et al. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids. Hum Mol Genet. 2010;19:3557-65 pubmed publisher
  17. Jacobson S, Aleman T, Sumaroka A, Cideciyan A, Roman A, Windsor E, et al. Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations. Invest Ophthalmol Vis Sci. 2009;50:1886-94 pubmed publisher
    ..The transition zones are candidate sites for treatment, and laminar architecture and visual sensitivity are possible outcomes to assess safety and efficacy. ..
  18. Dai H, Zhang X, Zhao X, Deng T, Dong B, Wang J, et al. Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type II. Mol Vis. 2008;14:2067-75 pubmed
    ..Mutations in the USH2A gene have been shown to be responsible for most cases of USH2. To further elucidate the role of USH2A in USH2, mutation screening was undertaken in three Chinese families with USH2...
  19. Grati M, Kachar B. Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction. Proc Natl Acad Sci U S A. 2011;108:11476-81 pubmed publisher
    ..We propose that MYO7A, sans, and harmonin-b form the core components of the UTLD molecular complex. In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link. ..
  20. Maerker T, Van Wijk E, Overlack N, Kersten F, McGee J, Goldmann T, et al. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet. 2008;17:71-86 pubmed
    ..Since this structural specialization in amphibian photoreceptor cells defines a specialized membrane domain for docking and fusion of transport vesicles, we suggest a prominent role of the USH proteins in cargo shipment. ..
  21. Hilgert N, Kahrizi K, Dieltjens N, Bazazzadegan N, Najmabadi H, Smith R, et al. A large deletion in GPR98 causes type IIC Usher syndrome in male and female members of an Iranian family. J Med Genet. 2009;46:272-6 pubmed publisher
    ..A large GPR98 deletion of 136 017 bp segregates with USH2C in an Iranian family. To our knowledge, this is only the second report of a GPR98 mutation, and the first report on male subjects with USH2C and a GPR98 mutation. ..
  22. Ebermann I, Wiesen M, Zrenner E, Lopez I, Pigeon R, Kohl S, et al. GPR98 mutations cause Usher syndrome type 2 in males. J Med Genet. 2009;46:277-80 pubmed publisher
    ..GPR98 may have been excluded from systematic investigation in previous studies, and the proportion of patients with USH2C probably underestimated. GPR98 should be considered in patients with USH2 of both sexes. ..
  23. Isosomppi J, Vastinsalo H, Geller S, Heon E, Flannery J, Sankila E. Disease-causing mutations in the CLRN1 gene alter normal CLRN1 protein trafficking to the plasma membrane. Mol Vis. 2009;15:1806-18 pubmed
    ..Mutant CLRN1 proteins are mislocalized. We suggest that part of the pathogenesis of USH3 may be associated with defective intracellular trafficking as well as decreased stability of mutant CLRN1 proteins. ..
  24. Herrera W, Aleman T, Cideciyan A, Roman A, Banin E, Ben Yosef T, et al. Retinal disease in Usher syndrome III caused by mutations in the clarin-1 gene. Invest Ophthalmol Vis Sci. 2008;49:2651-60 pubmed publisher
    ..USH3A and USH2A share patterns of rod and cone dysfunction and retinal structural abnormalities. Peripheral function measurements showed USH3A to be more rapidly progressive than USH2A. ..
  25. Kaiserman N, Obolensky A, Banin E, Sharon D. Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2. Arch Ophthalmol. 2007;125:219-24 pubmed
    ..Understanding the mechanism by which different USH2A mutations cause either USH2 or RP may assist in the development of novel therapeutic approaches. ..
  26. Ahmed Z, Riazuddin S, Aye S, Ali R, Venselaar H, Anwar S, et al. Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome. Hum Genet. 2008;124:215-23 pubmed publisher
    ..1. ..
  27. Zou J, Luo L, Shen Z, Chiodo V, Ambati B, Hauswirth W, et al. Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Invest Ophthalmol Vis Sci. 2011;52:2343-51 pubmed publisher
    ..The combined hRK and AAV gene delivery system could be an effective gene therapy approach to treat retinal degeneration in USH2D patients. ..
  28. Ebermann I, Koenekoop R, Lopez I, Bou Khzam L, Pigeon R, Bolz H. 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. Eur J Hum Genet. 2009;17:80-4 pubmed publisher
  29. Boulouiz R, Li Y, Abidi O, Bolz H, Chafik A, Kubisch C, et al. Analysis of MYO7A in a Moroccan family with Usher syndrome type 1B: novel loss-of-function mutation and non-pathogenicity of p.Y1719C. Mol Vis. 2007;13:1862-5 pubmed
    ..07. This finding has an important impact for molecular diagnosis and genetic counseling in USH1B families. ..
  30. Smits B, Peters T, Mul J, Croes H, Fransen J, Beynon A, et al. Identification of a rat model for usher syndrome type 1B by N-ethyl-N-nitrosourea mutagenesis-driven forward genetics. Genetics. 2005;170:1887-96 pubmed
    ..In addition, we demonstrate proof of principle for the generation and cloning of human disease models in rat using ENU mutagenesis, providing good perspectives for systematic phenotypic screens in the rat. ..
  31. Sahly I, Dufour E, Schietroma C, Michel V, Bahloul A, Perfettini I, et al. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol. 2012;199:381-99 pubmed publisher
    ..We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients. ..
  32. Aller E, Jaijo T, García García G, Aparisi M, Blesa D, Diaz Llopis M, et al. Identification of large rearrangements of the PCDH15 gene by combined MLPA and a CGH: large duplications are responsible for Usher syndrome. Invest Ophthalmol Vis Sci. 2010;51:5480-5 pubmed publisher
  33. Aller E, Larrieu L, Jaijo T, Baux D, Espinos C, Gonzalez Candelas F, et al. The USH2A c.2299delG mutation: dating its common origin in a Southern European population. Eur J Hum Genet. 2010;18:788-93 pubmed publisher
    ..Our data confirm the common ancestral origin of the c.2299delG mutation. ..
  34. Jaijo T, Aller E, Aparisi M, Garcia Garcia G, Hernan I, Gamundi M, et al. Functional analysis of splicing mutations in MYO7A and USH2A genes. Clin Genet. 2011;79:282-8 pubmed publisher
    ..The fact that splicing mutations led to in-frame or out-of-frame alterations cannot explain phenotypic differences, thus, genotype-phenotype correlations cannot be inferred. ..
  35. Adato A, Lefevre G, Delprat B, Michel V, Michalski N, Chardenoux S, et al. Usherin, the defective protein in Usher syndrome type IIA, is likely to be a component of interstereocilia ankle links in the inner ear sensory cells. Hum Mol Genet. 2005;14:3921-32 pubmed
    ..e. the disruption of hair bundle links-mediated adhesion forces that are essential for the proper organization of growing hair bundles. ..
  36. Vastinsalo H, Isosomppi J, Aittakorpi A, Sankila E. Two Finnish USH1B patients with three novel mutations in myosin VIIA. Mol Vis. 2006;12:1093-7 pubmed
    ..This is the first molecular genetic study of USH1 in Finland. We have found three new pathological mutations causing either premature termination of translation or replacement of an evolutionary conserved MYO7A amino acid. ..
  37. Jaijo T, Aller E, Beneyto M, Najera C, Graziano C, Turchetti D, et al. MYO7A mutation screening in Usher syndrome type I patients from diverse origins. J Med Genet. 2007;44:e71 pubmed
  38. El Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci. 2005;118:4593-603 pubmed
    ..In particular, myosin VIIa could act at the interface between microtubule- and actin-based transport. ..
  39. Williams D, Lopes V. The many different cellular functions of MYO7A in the retina. Biochem Soc Trans. 2011;39:1207-10 pubmed publisher
    ..It is likely that the progressive retinal degeneration that occurs in Usher syndrome 1B patients results from a combination of cellular defects in the RPE and photoreceptor cells. ..
  40. Roux A, Faugère V, Le Guédard S, Pallares Ruiz N, Vielle A, Chambert S, et al. Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. J Med Genet. 2006;43:763-8 pubmed
    ..Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis. ..
  41. Aarnisalo A, Pietola L, Joensuu J, Isosomppi J, Aarnisalo P, Dinculescu A, et al. Anti-clarin-1 AAV-delivered ribozyme induced apoptosis in the mouse cochlea. Hear Res. 2007;230:9-16 pubmed
    ..This result may be due to the injection technique, the promoter used, or tropism of the AAV serotype 2 viral vector. These results suggest the role of apoptosis in the progression of USH3A hearing loss warrants further evaluation. ..
  42. Lopes V, Gibbs D, Libby R, Aleman T, Welch D, Lillo C, et al. The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65. Hum Mol Genet. 2011;20:2560-70 pubmed publisher
    ..Together, the results support a role for MYO7A in the translocation of RPE65, illustrating the involvement of a molecular motor in the spatiotemporal organization of the retinoid cycle in vision. ..
  43. Dreyer B, Brox V, Tranebjaerg L, Rosenberg T, Sadeghi A, Moller C, et al. Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Hum Mutat. 2008;29:451 pubmed publisher
    ..2%) families the USH phenotype could be explained by mutations in the USH3A gene. The results presented here provide a comprehensive picture of the genetic aetiology of Usher syndrome type IIA in Scandinavia as it is known to date. ..
  44. Flores Guevara R, Renault F, Loundon N, Marlin S, Pelosse B, Momtchilova M, et al. Usher syndrome type 1: early detection of electroretinographic changes. Eur J Paediatr Neurol. 2009;13:505-7 pubmed publisher
    ..Electroretinogram showed retinopathy in young children with Usher syndrome type 1, even in the absence of fundoscopic signs of retinal degeneration. ..
  45. Nakanishi H, Ohtsubo M, Iwasaki S, Hotta Y, Mizuta K, Mineta H, et al. Identification of 11 novel mutations in USH2A among Japanese patients with Usher syndrome type 2. Clin Genet. 2009;76:383-91 pubmed publisher
    ..7% of mutated alleles; it is thus a frequent mutation in Japanese patients. Hence, mutation screening for c.8559-2A>G in USH2A may prove very effective for the early diagnosis of USH2. ..
  46. Peng Y, Zallocchi M, Wang W, Delimont D, Cosgrove D. Moderate light-induced degeneration of rod photoreceptors with delayed transducin translocation in shaker1 mice. Invest Ophthalmol Vis Sci. 2011;52:6421-7 pubmed publisher
    ..Importantly, USH1B animal models are likely vulnerable to light-induced photoreceptor damage, even under moderate light. ..
  47. Watanabe S, Umeki N, Ikebe R, Ikebe M. Impacts of Usher syndrome type IB mutations on human myosin VIIa motor function. Biochemistry. 2008;47:9505-13 pubmed publisher
    ..Taken together, the results suggest that the mutations responsible for USH1B cause the complete loss of the actin-activated ATPase activity or the reduction of duty ratio of myosin VIIa. ..
  48. Aparisi M, García García G, Jaijo T, Rodrigo R, Graziano C, Seri M, et al. Novel mutations in the USH1C gene in Usher syndrome patients. Mol Vis. 2010;16:2948-54 pubmed
    ..5% of USH1 disease in patients of Spanish origin (considering the total cohort of 65 Spanish USH1 patients since 2005), indicating that USH1C is a rare form of USH in this population. ..
  49. Williams D, Aleman T, Lillo C, Lopes V, Hughes L, Stone E, et al. Harmonin in the murine retina and the retinal phenotypes of Ush1c-mutant mice and human USH1C. Invest Ophthalmol Vis Sci. 2009;50:3881-9 pubmed publisher
    ..Perhaps the human disease is simply more aggressive than that in the mouse. Alternatively, the dfcr mouse may be a model for nonsyndromic deafness, due to the nonpathologic effect of its mutation on the retinal isoforms. ..
  50. Gibbs D, Diemer T, Khanobdee K, Hu J, Bok D, Williams D. Function of MYO7A in the human RPE and the validity of shaker1 mice as a model for Usher syndrome 1B. Invest Ophthalmol Vis Sci. 2010;51:1130-5 pubmed publisher
    ..Although shaker1 retinas do not undergo degeneration, correction of mutant phenotypes in the shaker1 RPE represents a valid preclinical test for potential therapeutic treatments. ..
  51. Bonnet C, El Amraoui A. Usher syndrome (sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches. Curr Opin Neurol. 2012;25:42-9 pubmed publisher
    ..Efforts to improve clinical diagnosis have been successful. Yet, despite some encouraging results, further development of therapeutic approaches is necessary to ultimately treat this dual sensory defect. ..
  52. Overlack N, Goldmann T, Wolfrum U, Nagel Wolfrum K. Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination. Invest Ophthalmol Vis Sci. 2012;53:4140-6 pubmed publisher
    ..We provide further evidence that the ZFN technology holds great potential to recover disease-causing mutations in inherited retinal disorders. ..
  53. Schwander M, Lopes V, Sczaniecka A, Gibbs D, Lillo C, Delano D, et al. A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells. J Neurosci. 2009;29:15810-8 pubmed publisher
    ..Our findings also suggest that MYO7A mutations can lead to tissue-specific effects on protein levels, which may explain why some mutations in MYO7A lead to deafness without retinal impairment. ..