2026-05-20 | The UNC45A–MYO5B Axis in Enterohepatic Disorders
Defects in epithelial polarity and apical trafficking underlie a spectrum of rare enterohepatic disorders, including microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC/PFIC). This thesis investigates the molecular relationship between the myosin co-chaperone UNC45A and the motor protein MYO5B, two proteins associated with overlapping intestinal and hepatic phenotypes.
Using intestinal epithelial and hepatocellular models, this work demonstrates that UNC45A is required for MYO5B protein stability and proper Rab11A-dependent apical recycling trafficking. Loss of UNC45A disrupts epithelial polarity, impairs microvillus formation, and induces MVID-like cellular defects. Mechanistic studies further show that specific UNC45A variants impair protein stability and chaperone-associated trafficking pathways. In addition, this thesis explores the pathogenesis of MYO5B-associated cholestasis and evaluates the therapeutic potential of ileal bile acid transporter inhibition in UNC45A-associated cholestatic disease.
Together, these findings establish a functional UNC45A–MYO5B axis linking rare enteropathic and cholestatic disorders at the molecular level and provide new insights into the regulation of epithelial polarity and apical membrane trafficking in the enterohepatic system.
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2026-02-12 | Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.
Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear. To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
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2025-12-08 | Microvillus Inclusion Disease: Successful Treatment of Severe Hyponatremia With High-Dose Fludrocortisone via a Possible Gut-Mediated Mechanism.
Microvillus inclusion disease (MVID) is a rare congenital enteropathy marked by severe secretory diarrhea and malabsorption due to microvillous atrophy secondary to accumulation of secretory granules in the apical cytoplasm of enterocytes. Management is supportive with parenteral nutrition and emergent management of acute electrolyte disturbances. We report an 8-month-old male infant with genetically confirmed MVID (MYO5B mutation) who developed life-threatening hyponatremia (serum sodium 118 mmol/L) despite maximal sodium supplementation (>300 mmol/d = 49 mmol/kg/d) and negligible urinary sodium level. High-dose fludrocortisone (100 mcg bid; 28.4 mcg/kg/d) successfully restored serum sodium levels and reduced stool output, with normalization of renin and aldosterone, without adverse effects. This case demonstrates a potential therapeutic benefit of gastrointestinal mineralocorticoid receptor agonism in managing severe hyponatremia in patients with MVID during periods of acute decompensation.
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