Myosin 5B-Associated Cholestatic Liver Disease Cholestatic liver disease (CLD) is characterized by an increase in the serum concentrations of compounds that are normally excreted with bile, such as bile acids and bilirubin. (1) CLD clinically manifest with cholestasis, jaundice, and pruritis. Diagnosis involves evaluation of the patient's clinical manifestations, exclusion of common causes of childhood cholestasis, and analyses of blood biochemistry and liver histology. (1) One blood marker that aids in the differential diagnosis of liver diseases is gamma-glutamyltransferase (GGT), a liver enzyme which is typically elevated in serum upon liver damage. The best known CLDs characterized by low/normal GGT are the benign recurrent and progressive forms of familial intrahepatic cholestasis (BRIC/PFIC), which are caused by mutations in the adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) gene encoding the ATP8B1 protein (BRIC/PFIC1) or in the adenosine triphosphate-binding cassette family B member 11 (ABCB11) gene encoding the canalicular bile salt export pump (BSEP) (BRIC/PFIC2). (2,3) In hepatocytes, ATP8B1 and BSEP are localized to the apical bile canalicular domain, where they contribute to biliary secretion. When mutated as in PFIC1/2 patients, the respective proteins are less expressed or mislocalized and/or display impaired activity, leading to defective biliary secretion and, consequently, cholestasis. (2,3) Since 2017 four independent reports have identified in total 30 different myosin 5B (MYO5B) mutations in 22 patients with non-microvillus inclusion disease (MVID) who were diagnosed with intermittent, recurrent, or progressive cholestasis presenting with jaundice, pruritus, hepatomegaly, and low/normal serum levels of GGT (Fig. 1; Supporting Table S1). These patients tested negative for mutations in other PFIC-associated genes. (4-7) MYO5B mutations may account for approximately 20% of pediatric patients with idiopathic low-GGT intrahepatic cholestasis. (8)
