NR1H4 – Progressive Familial Intrahepatic Cholestasis Type 5

Progressive familial intrahepatic cholestasis type 5 (PFIC5; MONDO:0014884) is a severe autosomal recessive liver disorder characterized by early-onset low-γ-glutamyl transferase cholestasis, coagulopathy, hyperammonemia, and failure to thrive. Causative biallelic variants in NR1H4 (HGNC:7967), encoding the farnesoid X receptor (FXR), disrupt bile acid homeostasis and lead to hepatocellular injury (PMID:38641832).

A retrospective multi-patient study identified 13 unrelated PFIC5 probands harboring biallelic NR1H4 variants, including eight homozygous and five compound heterozygous genotypes, and reported 13 distinct missense and splice–site alterations affecting FXR function (PMID:38641832). The spectrum comprises predominantly coding missense changes clustered within the ligand-binding domain, exemplified by c.527G>A (p.Arg176Gln), which impairs receptor activation and target gene regulation. All patients presented with neonatal jaundice (12/13), cholestasis (13/13), elevated α-fetoprotein (11/11), and coagulopathy (11/11).

Inheritance is autosomal recessive, consistent with segregation of biallelic variants in unrelated families. Although extended pedigree data are limited, the uniform presentation across multiple kindreds supports complete penetrance of pathogenic alleles when inherited in trans.

Functional concordance is demonstrated by FXR knockout mice, which develop spontaneous cholestasis, impaired bile salt export, and hepatocellular damage mirroring human PFIC5 (PMID:16446356). Loss-of-function FXR variants abrogate transcriptional activation of bile acid transporter genes, confirming haploinsufficiency as the pathogenic mechanism.

Mechanistically, FXR normally senses bile acids and induces expression of key transporters (e.g., BSEP, SHP) to maintain enterohepatic balance. Biallelic NR1H4 variants disrupt this feedback loop, leading to intrahepatic bile acid accumulation, hepatocyte apoptosis, and progressive liver injury.

Integration of robust genetic and experimental data establishes NR1H4 as a moderate-to-strongly validated PFIC5 gene. Genetic testing for NR1H4 variants enables definitive diagnosis, informs prognosis, and guides early therapeutic interventions including liver transplantation.

Key Take-home: Biallelic loss-of-function NR1H4 variants cause PFIC5 through FXR deficiency–mediated cholestasis, underscoring the clinical utility of FXR sequencing in neonatal cholestatic liver disease.

References

• Unspecified Journal • 2024 • Clinical studies on progressive familial intrahepatic cholestasis type 5 caused by mutations in NR1H4 PMID:38641832
• American Journal of Physiology. Endocrinology and Metabolism • 2006 • The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice PMID:16446356

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