USH1C – Usher syndrome type 1C

Usher syndrome type 1C is an autosomal recessive disorder characterized by congenital profound sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia. The USH1C gene encodes the PDZ-domain‐containing scaffolding protein harmonin, which is essential for hair cell mechanoelectrical transduction and photoreceptor synaptic integrity. Loss‐of‐function variants in USH1C disrupt harmonin’s scaffolding roles in both the inner ear and the retina, leading to the clinical triad of Usher type 1C (USH1C; Usher syndrome type 1C).

Genetic evidence includes a novel homozygous frameshift variant c.238del (p.Ser80AlafsTer?) identified by whole‐exome sequencing in an 18-year-old female with congenital hearing loss and progressive retinitis pigmentosa (PMID:38470933). Genotype linkage in two unrelated New England families revealed distinct Acadian and Lebanese founder haplotypes at the USH1C locus among individuals with type 1C Usher syndrome (PMID:11239869). A third consanguineous Pakistani family was found to segregate a novel homozygous splice acceptor variant c.877-1G>A co-segregating with Usher syndrome type 1 features (PMID:33231815).

Variant spectrum is dominated by loss‐of‐function alleles, including frameshift and splice junction variants, and two independently arisen founder haplotypes. No pathogenic missense variants have been recurrently reported for the classic USH1C phenotype.

Functional assays demonstrate that harmonin isoforms a and c localize to photoreceptor synapses, and ERG studies in USH1C patients reveal rod- and cone-mediated sensitivity loss despite preserved central laminar architecture (PMID:19324851). The dfcr mouse model harboring an Ush1c mutation lacks a retinal phenotype, highlighting species differences in harmonin isoform expression.

Therapeutic rescue studies show that the nonsense variant c.91C>T (p.Arg31Ter) undergoes aminoglycoside-mediated read-through with the synthetic derivative NB30 in retinal explants, restoring harmonin function in GST pull-down and F-actin bundling assays with minimal toxicity (PMID:20671281).

Collectively, three unrelated probands, two founder haplotypes, and concordant functional data support a Moderate clinical validity classification for USH1C in Usher syndrome type 1C. Key take-home: genetic testing for USH1C loss-of-function variants enables definitive diagnosis and informs emerging read-through therapeutic strategies.

References

• Retinal cases & brief reports • 2024 • Co-occurring Usher syndrome Type 1 and Renal Failure. PMID:38470933
• American journal of ophthalmology • 2001 • Two families from New England with usher syndrome type IC with distinct haplotypes. PMID:11239869
• Molecular biology reports • 2020 • Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss. PMID:33231815
• Investigative ophthalmology & visual science • 2009 • Harmonin in the murine retina and the retinal phenotypes of Ush1c-mutant mice and human USH1C. PMID:19324851
• Investigative ophthalmology & visual science • 2010 • Beneficial read-through of a USH1C nonsense mutation by designed aminoglycoside NB30 in the retina. PMID:20671281

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