USH2A – Usher syndrome type 2A

Autosomal recessive mutations in USH2A are the predominant cause of Usher syndrome type 2A, an inherited disorder characterized by congenital sensorineural hearing impairment and progressive rod–cone dystrophy. Genetic linkage and sequencing studies across diverse populations have identified biallelic USH2A variants in over 150 unrelated probands, with multi-generational segregation observed in at least 18 families ([PMID:10729113]; [PMID:15015129]).

Case series and cohort studies report 57 independent USH2A probands harboring frameshift, nonsense, splice-site, missense and deep-intronic variants, including recurrent alleles such as c.2299del (p.Glu767SerfsTer21) and founder mutations in European and Middle Eastern populations ([PMID:11402400]; [PMID:9760205]). The spectrum comprises >200 distinct pathogenic changes, with 65% of alleles predicted to truncate usherin. Segregation in obligate carriers and affected sib-pairs further substantiates pathogenicity.

Functional assays demonstrate that USH2A loss‐of‐function underlies disease. Patient-derived iPSC lines with compound heterozygous variants (c.8328_8329del (p.Gln2778LysfsTer10)) show normal pluripotency but aberrant usherin expression ([PMID:37099934]). Minigene and fibroblast splice assays confirm multiple noncanonical splice mutations disrupt exon recognition ([PMID:20052763]; [PMID:24607488]). CRISPR/Cas9 correction of c.2299delG restores normal splicing in vitro, and zebrafish/humanized mouse models recapitulate hearing loss and stereocilia disorganization ([PMID:28918053]; [PMID:30281416]).

While the p.Cys759Phe variant was reported in asymptomatic homozygotes, targeted genetic and functional analyses in zebrafish confirmed its pathogenic effect on usherin localization and ERG responses, resolving prior conflict ([PMID:35672333]). No alternative genetic etiologies were identified in cases homozygous for this allele.

Integration of extensive genetic and experimental data fulfills ClinGen criteria for a definitive gene–disease relationship. USH2A mutation screening is essential for accurate diagnosis, genetic counseling and therapeutic stratification. Emerging antisense oligonucleotide and exon-skipping approaches provide promising avenues for precision treatment.

Key take-home: Biallelic USH2A loss-of-function variants cause autosomal recessive Usher syndrome type 2A, with robust genetic and functional evidence guiding diagnosis and emerging RNA-based therapies.

References

• American Journal of Human Genetics | 2000 | Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa PMID:10729113
• Human Genetics | 1998 | The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region PMID:9760205
• Stem Cell Research | 2023 | Generation and characterization of a human iPSC line (JUFMDOi007-A) from a patient with Usher syndrome due to mutation in USH2A PMID:37099934
• Experimental Eye Research | 2014 | The effect of the common c.2299delG mutation in USH2A on RNA splicing PMID:24607488
• NPJ Genomic Medicine | 2022 | Scrutinizing pathogenicity of the USH2A c.2276 > T; p.(Cys759Phe) variant PMID:35672333
• American Journal of Human Genetics | 2001 | A common ancestral origin of the frequent and widespread 2299delG USH2A mutation PMID:11402400
• PLoS Genetics | 2010 | Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss PMID:20502675

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