Overview
Gene (OMIM No.) |
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Function of gene/protein |
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Clinical phenotype (OMIM phenotype no.) |
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Inheritance |
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Ocular features | |
Visual function |
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Systemic features |
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Key investigations |
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Molecular diagnosis | Next generation sequencing
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Management |
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Therapies under research |
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Further information |
Additional information
USH2A has a diverse spectrum of mutations, including nonsense, missense, indels and complex rearrangements, that can be found along the length of the gene. Several studies have provided evidence of genotype-phenotype correlations associated with USH2A; in general, variants that are more likely to allow residual protein function e.g missense mutations, appear to preserve hearing in patients.[5-10]
1) Usher syndrome type 2
The most frequent USH2A mutation associated with Usher syndrome type 2 is the c.2299delG p.(Glu767Serfs*21) variant in exon 13.[11,12] Patients with a combination of two truncating mutations (i.e. frameshift, nonsense) or two missense variants in the N-terminal domain of USH2A are most commonly affected by Usher syndrome type 2.[5,7,13]. Severe hearing impairment has been associated with truncating variants in USH2A.[6,8,10,14]
2) Autosomal recessive retinitis pigmentosa (RP)
The common USH2A mutation associated with autosomal recessive RP is the missense variant c.2276G>T p.(Cys759Phe).[5,15] The presence of the p.(Cys759Phe) variant in a homozygous state or in combination with other USH2A missense mutations has been associated with isolated autosomal recessive RP or RP with late onset hearing loss.[8]
Multimodal imaging

References
- Fuster-Garcia C, Garcia-Garcia G, Gonzalez-Romero E, et al. USH2A Gene Editing Using the CRISPR System. Mol Ther Nucleic Acids. 2017;8:529-541
- Sanjurjo-Soriano C, Erkilic N, Baux D, et al. Genome Editing in Patient iPSCs Corrects the Most Prevalent USH2A Mutations and Reveals Intriguing Mutant mRNA Expression Profiles. Mol Ther Methods & Clin Dev. 2020;17:156-173
- Neuhaus C, Eisenberger T, Decker C, et al. Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. Mol Genet & Genomic Med. 2017;5(5):531-552
- Samanta A, Stingl K, Kohl S, Ries J, Linnert J, Nagel-Wolfrum K. Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations. Int J Mol Sci. 2019;20(24)
- Lenassi E, Vincent A, Li Z, et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015;23(10):1318-1327
- Blanco-Kelly F, Jaijo T, Aller E, et al. Clinical aspects of Usher syndrome and the USH2A gene in a cohort of 433 patients. JAMA Ophthalmol. 2015;133(2):157-164
- Pierrache LH, Hartel BP, van Wijk E, et al. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2016;123(5):1151-1160
- Pérez-Carro R, Blanco-Kelly F, Galbis-Martínez L, et al. Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families. PLoS One. 2018;13(6):e0199048
- Molina-Ramírez LP, Lenassi E, Ellingford JM, et al. Establishing Genotype-phenotype Correlation in USH2A-related Disorders to Personalize Audiological Surveillance and Rehabilitation. Otol Neurotol. 2020
- Hartel BP, Lofgren M, Huygen PL, et al. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa. Hear Res. 2016;339:60-68
- Le Quesne Stabej P, Saihan Z, Rangesh N, et al. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012;49(1):27-36
- Dreyer B, Tranebjaerg L, Brox V, et al. A common ancestral origin of the frequent and widespread 2299delG USH2A mutation. Am J Hum Genet. 2001;69(1):228-234
- Gao FJ, Wang DD, Chen F, et al. Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease. Br J Ophthalmol. 2020
- Lee SY, Joo K, Oh J, et al. Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation. Clin Exp Otorhinolaryngol. 2019
- Rivolta C, Sweklo EA, Berson EL, Dryja TP. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000;66(6):1975-1978