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USH2A gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Large transmembrane protein
  • Component of the ankle links in the stereocilia of the developing inner ear hair cells
  • Required for correct postnatal development of hair cell stereocilia
  • Localises to the periciliary membrane complex at the photoreceptor connecting cilium
  • May be involved in intracellular transport in photoreceptors
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
Ocular features
Visual function
  • Nyctalopia starting around adolescence or later
  • Peripheral visual field loss
  • Loss of central and colour vision in later life
  • Onset of RP is usually within the first two decades of life in Usher syndrome type 2A
  • Visual field loss more severe in Usher syndrome type 2A compared to patients with isolated USH2A-RP
Systemic features
  • Congenital, bilateral, sensorineural hearing loss; mild to moderate in the low frequencies, and severe to profound in the high frequencies
  • Failed newborn hearing screen or hearing difficulties suspected in infancy
Key investigations
  • Newborn hearing screen – otoacoustic emission and automated auditory brainstem response
  • Pure tone audiometry
  • Electrophysiology
  • Fundus autofluorescence (FAF): a ring of hyper-AF in the macula
  • Optical coherence tomography (OCT): progressive loss of outer retinal structures which spares the fovea initially; cystoid macular oedema may be detected
  • Kinetic perimetry
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal and deafness)
  • Whole exome sequencing
  • Whole genome sequencing
  • Targeted exome sequencing
Management
Therapies under research
Further information

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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]

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Multimodal imaging

Multimodal imaging of a patient with biallelic USH2A variants. The fundal phenotype is of typical retinitis pigmentosa (A). There is a central ring of hyperautofluorescence on FAF imaging (B), demarcating the border between degenerated and preserved outer retinal layers (C)

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References

  1.  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
  2.  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
  3.  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
  4.  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)
  5.  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
  6.  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
  7.  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
  8.  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
  9.  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
  10.  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
  11.  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
  12.  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
  13.  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
  14.  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
  15.  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

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Updated on January 24, 2021
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