USH1G – Usher syndrome type 1

Usher syndrome type 1 is an autosomal recessive disorder characterized by congenital profound sensorineural hearing loss and early-onset retinitis pigmentosa. Biallelic pathogenic variants in USH1G encoding the scaffold protein SANS disrupt inner ear hair cell function and photoreceptor maintenance.

In an Israeli Arab cohort, haplotype analysis and genome-wide homozygosity mapping identified a homozygous nonsense variant c.805C>T (p.Arg269Ter) in USH1G in one consanguineous family (PMID:22219650). This supports an autosomal recessive inheritance mode with loss-of-function mechanism.

Targeted exome sequencing of 18 Algerian USH patients detected one USH1G in-frame deletion p.Ala397del within the SAM domain affecting the USH1G–USH1C interface in one homozygous proband (PMID:27583663). Noncanonical splice site analysis in hereditary deafness families revealed c.164+5G>A in two simplex AR pedigrees causing aberrant exon retention in USH1G transcripts (PMID:34956325).

Collectively, four unrelated probands across three cohorts harbor biallelic USH1G variants, with autosomal recessive segregation supported by homozygosity mapping and family studies. Affected relatives beyond index cases have not been extensively reported, reflecting the rarity of USH1G-related pedigrees.

The variant spectrum comprises multiple truncating alleles and splice-site alterations, exemplified by c.805C>T (p.Arg269Ter) and c.164+5G>A, consistent with a loss-of-function disease mechanism.

Functional studies demonstrate that SANS interacts with USH2A and whirlin to form periciliary protein complexes in photoreceptors, a process disrupted by SANS truncations; translational read-through of p.Ser243Ter restores scaffold function (PMID:28137943). USH1G variants also impair U4/U6.U5 snRNP trafficking via perturbed binding to PRPF6 and PRPF31 (PMID:38139438) and alter nuclear-cytoplasmic shuttling by disrupting NLS/NES sequences (PMID:39594604).

These genetic and functional data converge to classify the USH1G–Usher syndrome type 1 association as Moderate strength, affirming the clinical utility of USH1G testing in congenital deafness and retinitis pigmentosa. Key Take-home: Pathogenic biallelic USH1G variants cause autosomal recessive Usher syndrome type 1, guiding genetic diagnosis and informing therapeutic strategies.

References

• Molecular Vision • 2011 • Novel mutations of MYO7A and USH1G in Israeli Arab families with Usher syndrome type 1. PMID:22219650
• PLOS One • 2016 • Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome. PMID:27583663
• Frontiers in Genetics • 2021 • Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness. PMID:34956325
• Human Molecular Genetics • 2017 • Characterization of the ternary Usher syndrome SANS/ush2a/whirlin protein complex. PMID:28137943
• International Journal of Molecular Sciences • 2023 • Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome. PMID:38139438
• Cells • 2024 • Nuclear-Cytoplasmic Shuttling of the Usher Syndrome 1G Protein SANS Differs from Its Paralog ANKS4B. PMID:39594604

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