USH1C – Usher syndrome type 1

Usher syndrome type 1 (USH1) is an autosomal recessive disorder characterized by congenital profound sensorineural hearing loss, vestibular dysfunction, and prepubertal-onset retinitis pigmentosa. USH1C (HGNC:12597) encodes harmonin, a scaffold protein essential for hair cell mechanotransduction and photoreceptor synapse integrity. Biallelic pathogenic variants in USH1C underlie Usher syndrome type 1C (MONDO:0010168), leading to combined auditory and visual deficits.

Initial evidence arose from three affected individuals from two consanguineous families presenting with hyperinsulinism, enteropathy, renal tubular dysfunction, and profound deafness due to a homozygous 122-kb contiguous deletion encompassing USH1C ([PMID:10973248]). Subsequent screening of 128 USH1 probands identified seven Acadian patients homozygous for the c.216G>A (p.Val72=) founder allele and two non-Acadian probands with the same variant, confirming a population-specific founder effect ([PMID:12630964]).

Additional case series in the UK (14 USH1 patients) detected c.238dup (p.Arg80ProfsTer) in two probands, one homozygous and one heterozygous, supporting a broader distribution of loss-of-function alleles ([PMID:12702164]). In French Canadian Quebec patients, 60% (nine of fifteen) carried the c.216G>A allele, accounting for 40% of disease alleles and a carrier frequency compatible with a 0.5% risk of retinal degeneration in congenitally deaf children ([PMID:17407589]). Rare USH1C mutations have also been identified in Israeli Arab, Algerian, and other populations, underscoring global allelic heterogeneity.

The variant spectrum encompasses nonsense, frameshift, splice-site, and canonical splice-disrupting synonymous changes, with recurrent alleles c.216G>A (p.Val72=) and c.238dup (p.Arg80ProfsTer) in founder and sporadic contexts. Over 25 unrelated probands with biallelic USH1C variants have been reported, demonstrating autosomal recessive segregation across at least eight families.

Functional studies reveal harmonin isoforms a and c localized at photoreceptor synapses, with dfcr mutant mice showing normal retinal morphology but human patients exhibiting central-to-peripheral ERG and OCT abnormalities ([PMID:19324851]). In vitro assays demonstrated efficient read-through of the USH1C p.Arg31Ter mutation by synthetic aminoglycoside NB30, restoring harmonin scaffold function with favorable biocompatibility ([PMID:20671281]). Zinc-finger nuclease–mediated repair of the p.Arg31Ter mutation reinstated gene and protein expression, validating a targeted therapeutic approach ([PMID:22661463]).

No conflicting evidence disputing the USH1C–Usher syndrome type 1C association has been reported. The cumulative genetic and experimental data satisfy ClinGen criteria for a Strong gene–disease relationship.

Key take-home: Biallelic loss-of-function and splice-disrupting variants in USH1C cause autosomal recessive Usher syndrome type 1C, with founder alleles in Acadian and Quebec populations and robust functional concordance, supporting reliable molecular diagnosis and therapeutic targeting.

References

• Nature genetics • 2000 • A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. PMID:10973248
• Clinical genetics • 2003 • USH1C: a rare cause of USH1 in a non-Acadian population and a founder effect of the Acadian allele. PMID:12630964
• Clinical genetics • 2003 • The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK. PMID:12702164
• Genome biology • 2007 • Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population. PMID:17407589
• 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
• Investigative ophthalmology & visual science • 2012 • Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination. PMID:22661463

Evidence Based Scoring (AI generated)