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

## TL;DR

The study finds that BSEP localization in MYO5B-related cholestasis depends on MYO5B genotype but does not affect clinical outcomes, suggesting treatment should focus on clinical signs rather than genetic or immunohistochemical data.

## Contribution

This work systematically reviews MYO5B-associated cholestasis cases and clarifies the relationship between MYO5B genotype, BSEP localization, and clinical outcomes.

## Key findings

- Aberrant BSEP localization correlates with absence of truncating MYO5B variants.
- Clinical outcomes are similar regardless of BSEP localization.
- MYO5B and ABCB11 deficiency-associated FIC have distinct clinical and biochemical profiles.

## Abstract

What are the main findings?
Aberrant BSEP localization correlates with the absence of truncating nonsense or frameshift variants in MYO5B.Clinical phenotypes do not differ between cases with normal versus aberrant BSEP localization.

Aberrant BSEP localization correlates with the absence of truncating nonsense or frameshift variants in MYO5B.

Clinical phenotypes do not differ between cases with normal versus aberrant BSEP localization.

What is the implication of the main findings?
The clinical picture is more relevant than genotype or immunohistochemistry findings to guide management.

The clinical picture is more relevant than genotype or immunohistochemistry findings to guide management.

Variants of the MYO5B 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 MYO5B-associated cholestasis implicates faulty trafficking of the ABCB11-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 MYO5B-associated FIC. We present a focused systematic narrative review of all cases of MYO5B variant-associated isolated FIC reported in the MEDLINE database. We assembled a comprehensive patient dataset and assessed clinical features of MYO5B-associated FIC, their relationship with MYO5B genotype, the clinical value and significance of BSEP abnormalities, and the relationship of MYO5B-associated FIC to ABCB11 variant-associated FIC. Our review revealed that aberrant BSEP localization correlated with the absence of one MYO5B 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 MYO5B 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.