USH1G – Usher syndrome type 1G

USH1G is implicated in autosomal recessive Usher syndrome type 1G, characterized by congenital sensorineural hearing loss and progressive retinitis pigmentosa. Homozygosity mapping in a Turkish consanguineous family yielded a maximum two-point LOD score of 4.07 at D17S801, delineating a 15-cM interval on 17q25.1-25.3 containing USH1G (PMID:16283141). Sequence analysis identified a homozygous missense variant c.1373A>T (p.Asp458Val) segregating with disease in two affected siblings and present in one of 64 additional families but absent or heterozygous in controls (PMID:16283141).

Functional studies demonstrate that p.Asp458Val disrupts the PDZ‐binding motif of SANS, impairing its interaction with harmonin and destabilizing the USH1/USH2 protein network in photoreceptors (PMID:28137943). Additional work shows that USH1G nonsense and splice‐site variants perturb SANS binding to PRPF6/PRPF31 in spliceosomal assembly and alter nuclear–cytoplasmic shuttling, underscoring a loss-of-function mechanism (PMID:38139438; PMID:39594604).

Key Take-home: USH1G loss-of-function variants cause autosomal recessive Usher syndrome type 1G, and molecular diagnosis informs prognosis and eligibility for emerging rescue therapies.

References

• Journal of molecular medicine (Berlin, Germany) • 2005 • A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome. PMID:16283141
• 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

Evidence Based Scoring (AI generated)