Adult-Onset BAAT p.Glu401Asp Mutation Linking Intrahepatic Cholestasis of Pregnancy to FXR-SREBP Dysregulation.

Authors

Dhiraj Agrawal, Ramesh R Avula, Shraddha Sonthalia, Swetha Kamath, Guru N Reddy

Published in

Journal of clinical and experimental hepatology. Volume 16. Issue 5. Pages 103605. Epub Jul 06, 2026.

Abstract

Intrahepatic cholestasis of pregnancy (ICP) affects 0.5-5.6 % of pregnancies and involves bile acid transport defects (ABCB11, ABCB4, ATP8B1). BAAT mutations classically cause neonatal familial hypercholanemia type 3 (FHCA3), with five previously identified pathogenic variants in the catalytic domains. We report a rare adult-onset homozygous BAAT missense mutation (c.1203G>T; p.Glu401Asp) in a 41-year-old Indian woman with third-trimester ICP, postpartum-persistent hypercholanemia, and severe hypertriglyceridemia. This novel BAAT substitution occurs at codon 401 (C-terminal, non-catalytic), yielding conflicting in silico predictions (CADD: 22.5 pathogenic vs. REVEL: 0.211 benign). However, classified as a Variant of Uncertain Significance, its homozygosity and phenotypic correlation support plausibility, pending family segregation, bile acid profiling, or functional assays. Proposedly unconjugated primary bile acids impair ileal FXR activation, thereby disrupting FGF19-SHP-mediated repression of SREBP-1c lipogenesis, a process compounded by insulin resistance. This case represents a rare adult BAAT-ICP association and BAAT-related FXR-SREBP dysregulation, expanding the low-GGT cholestasis spectrum per EASL guidelines. Glycocholic acid and FXR agonists may offer targeted therapies.

PMID:
42495515
Bibliographic data and abstract were imported from PubMed on 24 Jul 2026.

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