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USP45 – Leber congenital amaurosis

Leber congenital amaurosis (LCA) is an early-onset, severe inherited retinal dystrophy characterized by profound visual impairment. In two Chinese families with LCA, whole-exome sequencing identified homozygous variants in USP45: c.1636A>T (p.Lys546Ter) and c.935G>A (p.Arg312Gln) (PMID:30573563). Both variants are absent from large control cohorts and affect conserved residues in the deubiquitylase domain.

Segregation analysis confirmed that each variant segregates with disease in two unrelated probands with no additional affected relatives reported (PMID:30573563). Immunohistochemistry showed enriched USP45 expression in the inner segments of human and zebrafish photoreceptors, supporting a retinal-specific role.

Functional assays in zebrafish knockdown models recapitulated abnormal retinal development and photoreceptor defects, which were fully rescued by wild-type usp45 mRNA (PMID:30573563). Targeted Usp45 knockout mice exhibited abnormal electroretinography responses mirroring human LCA.

At the molecular level, USP45 interacts with and deubiquitylates the ERCC1–XPF endonuclease complex; USP45-deficient cells show impaired UV-induced DNA repair and hypersensitivity to cross-linking agents (PMID:25538220). Defective ERCC1 recruitment to damage foci elucidates a mechanism by which USP45 maintains photoreceptor integrity.

No conflicting reports have been described. Together, genetic and experimental datasets provide strong evidence that biallelic USP45 mutations cause autosomal recessive Leber congenital amaurosis.

Key Take-home: USP45 is indispensable for photoreceptor maintenance and should be included in genetic testing panels for LCA.

References

  • Journal of medical genetics • 2019 • Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. PMID:30573563
  • The EMBO journal • 2015 • USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses. PMID:25538220

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

2 unrelated probands (families) ([PMID:30573563]); concordant functional data in zebrafish and mouse models

Genetic Evidence

Moderate

Biallelic USP45 variants identified in 2 unrelated families with homozygous LoF and missense alleles segregating with disease ([PMID:30573563])

Functional Evidence

Moderate

Zebrafish knockdown with mRNA rescue and mouse knockout recapitulate LCA phenotype; in vitro deubiquitylation assays confirm mechanism ([PMID:30573563]; [PMID:25538220])