TJP2 – Progressive Familial Intrahepatic Cholestasis Type 4

The tight junction protein-2 gene (TJP2) encodes the zonula occludens-2 (ZO-2) protein, crucial for hepatic tight junction integrity. Biallelic pathogenic variants in TJP2 cause Progressive Familial Intrahepatic Cholestasis type 4 (PFIC4), an autosomal recessive cholestatic liver disease. PFIC4 manifests in infancy or childhood with pruritus, splenomegaly, and conjugated hyperbilirubinemia but normal gamma-glutamyl transferase levels. Clinical hallmarks include jaundice, elevated transaminases, and failure to thrive. Accurate genetic diagnosis informs management and family counseling. This summary integrates case series, segregation, and functional studies to define the TJP2–PFIC4 association.

Three unrelated probands were reported in individual case reports: a 15-year-old boy with compound heterozygous missense variants including p.Leu791Pro presenting with pruritus, clubbing, splenomegaly, and conjugated hyperbilirubinemia (PMID:32636225); a neonate homozygous for c.2417G>A (p.Trp806Ter) with severe cholestasis and intracranial bleeds (PMID:38090248); and a 12-year-old female with novel compound heterozygous missense variants presenting with persistent cholestasis (PMID:39697951). In all reports, autoimmune and viral etiologies were excluded, and direct genetic confirmation established PFIC4.

A multi-family study identified a homozygous missense variant c.1594G>C (p.Gly532Arg) in three consanguineous families encompassing nine affected children, each with early-onset intrahepatic cholestasis and low GGT activity (PMID:40251428). Segregation analysis confirmed co-segregation of the variant with disease status across families. In silico structural modeling predicted disruption of PDZ domain integrity concordant with clinical severity.

The variant spectrum in PFIC4 includes truncating alleles such as c.2417G>A (p.Trp806Ter), canonical splice alterations like c.2668-11A>G leading to exon skipping, and missense changes including p.Gly532Arg and p.Glu401Gly (c.1202A>G) disrupting protein stability (PMID:34504838). These alleles are absent or extremely rare in population databases, consistent with a recessive inheritance model. No founder variants have been identified to date.

Functional assays demonstrate that TJP2 pathogenic variants impair tight junction assembly and bile canaliculi formation. Minigene assays revealed exon skipping for the c.2180-5T>G splice variant (PMID:31696999), while CRISPR-Cas9 engineered cells harboring c.1202A>G exhibited mislocalization and increased nuclear ZO-2 (PMID:34504838). Patient-derived iPSC-hepatocyte models recapitulated canalicular membrane disruptions and altered bile acid transport (PMID:35284810), confirming haploinsufficiency as the likely disease mechanism.

Collectively, genetic evidence from six probands across four pedigrees, with segregation in nine additional relatives, alongside concordant functional studies, supports a Strong clinical validity classification for the TJP2–PFIC4 association. Genetic testing for TJP2 should be integrated into diagnostic workflows for unexplained pediatric cholestasis. Functional models offer platforms for mechanistic investigation and therapeutic development. Key take-home: Biallelic TJP2 variants are a well-validated cause of PFIC4, informing diagnosis, family counselling, and future research.

References

• BMJ Case Reports • 2020 • Progressive familial intrahepatic cholestasis type 4 in an Indian child: presentation, initial course and novel compound heterozygous mutation PMID:32636225
• Sultan Qaboos University Medical Journal • 2023 • Severe Neonatal Presentation of Progressive Familial Intrahepatic Cholestasis Type 4 in an Omani Infant PMID:38090248
• Cureus • 2024 • A Novel Compound Heterozygous Mutation in Progressive Familial Intrahepatic Cholestasis (PFIC) 4: A Rare Case Report With Literature Review PMID:39697951
• Journal of Human Genetics • 2025 • Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level PMID:40251428
• Human Mutation • 2020 • TJP2 hepatobiliary disorders: Novel variants and clinical diversity PMID:31696999
• Frontiers in Cell and Developmental Biology • 2021 • Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients PMID:34504838
• JHEP Reports: Innovation in Hepatology • 2022 • Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency PMID:35284810

Evidence Based Scoring (AI generated)