MYO5B Deficiency-Associated Cholestasis and the Role of the Bile Salt Export Pump

Variants of the <i>MYO5B</i> gene, which encodes the molecular motor protein myosin-Vb, have gained prominence as a causative factor in familial intrahepatic cholestasis (FIC). Understanding the disease mechanism is pivotal for therapy development and clinical decision-making. The prevailing theory for the mechanism underlying <i>MYO5B</i>-associated cholestasis implicates faulty trafficking of the <i>ABCB11</i>-encoded bile salt export pump (BSEP) in hepatocytes due to dysfunctional myosin-Vb. This is supported by cell and mouse studies. However, while BSEP localization was abnormal in some patients' liver biopsies, BSEP appeared normally localized in others, raising questions with regard to the role of BSEP in <i>MYO5B</i>-associated FIC. We present a focused systematic narrative review of all cases of <i>MYO5B</i> variant-associated isolated FIC reported in the MEDLINE database. We assembled a comprehensive patient dataset and assessed clinical features of <i>MYO5B</i>-associated FIC, their relationship with <i>MYO5B</i> genotype, the clinical value and significance of BSEP abnormalities, and the relationship of <i>MYO5B</i>-associated FIC to <i>ABCB11</i> variant-associated FIC. Our review revealed that aberrant BSEP localization correlated with the absence of one <i>MYO5B</i> allele carrying a truncating nonsense or frameshift variant. Notably, biochemical and clinical parameters including treatment outcome were indistinguishable between patients presenting with normal and aberrant BSEP localization. Further, myosin-Vb and BSEP deficiency-associated FIC patient cohorts showed distinct biochemical and clinical phenotypes, indicating different underlying mechanisms. This suggests that whether or not BSEP localization was abnormal depended on the <i>MYO5B</i> genotype without a predictable effect on clinical parameters and treatment response. Treatment decisions should be guided by clinical parameters rather than by genotype or immunohistochemistry findings.