USP53 – Low-GGT Intrahepatic Cholestasis

Ubiquitin-specific peptidase 53 (USP53) has emerged as a novel autosomal recessive cause of pediatric intrahepatic cholestasis (cholestasis). A single 7-month-old infant presented with intractable pruritus (HP:0000989) and progressive cholestasis; liver biopsy revealed portal and perivenular fibrosis with bland bilirubinostasis (PMID:34809518). Parents were asymptomatic heterozygotes, confirming biallelic inheritance.

Subsequent whole-exome sequencing in a cohort of 30 cholestasis patients without known mutations identified three homozygous USP53 variants, and targeted next-generation sequencing in an expanded sample yielded four additional patients from four unrelated families (PMID:33075013). Age at onset ranged from infancy to adolescence, with biochemically mild, intermittent cholestasis responsive to ursodeoxycholic acid. Liver fibrosis (HP:0001395) was universal in biopsied cases and splenomegaly (HP:0001744) was detected in five of seven by ultrasound.

In an independent cohort of low-GGT cholestasis (n=69), seven patients from seven unrelated families harbored ten predicted pathogenic USP53 variants including one canonical splice site (c.569+2>C), six nonsense/frameshift (e.g., c.169C>T (p.Arg57Ter)), and three missense changes (PMID:32124521). All affected individuals exhibited onset before 7 months, transient hyperbilirubinemia, giant-cell transformation, and perisinusoidal fibrosis. Ultrastructural studies demonstrated elongated hepatocyte tight junctions, suggesting phenocopy of TJP2 deficiency.

Across these cohorts and a single case report, 15 probands from 12 unrelated families have been reported with biallelic USP53 variants segregating with autosomal recessive cholestasis (PMID:34809518, PMID:33075013, PMID:32124521). Variant spectrum includes at least 12 loss-of-function and three missense alleles. One recurrent missense, c.725C>T (p.Pro242Leu), was observed in a consanguineous pedigree.

Mechanistic insights from biochemical and structural analyses demonstrate that USP53 is an active K63-linkage–specific deubiquitinase; patient-derived mutations abrogate catalytic activity and increase K63-linked ubiquitination of tight junction proteins (PMID:39587316). Loss of USP53 DUB function likely disrupts hepatocyte junction integrity, underpinning cholestatic pathology.

Collectively, the concordant genetic segregation, variant spectrum, consistent histopathology, and mechanistic DUB assays support a Strong gene-disease association. USP53 should be included in diagnostic panels for low-GGT intrahepatic cholestasis, guiding early intervention and family counseling.

References

• Pediatric and developmental pathology • 2022 • Biallelic Mutations in Ubiquitin-Specific Peptidase 53 (USP53) Causing Progressive Intrahepatic Cholestasis. Report of a Case With Review of Literature. PMID:34809518
• Journal of Pediatric Gastroenterology and Nutrition • 2021 • Cholestasis Due to USP53 Deficiency. PMID:33075013
• Liver International • 2020 • Low-GGT intrahepatic cholestasis associated with biallelic USP53 variants: Clinical, histological and ultrastructural characterization. PMID:32124521
• Nature Chemical Biology • 2025 • Discovery and mechanism of K63-linkage-directed deubiquitinase activity in USP53. PMID:39587316

Evidence Based Scoring (AI generated)