Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome

Hum Mutat. 2019 Dec;40(12):2247-2257. doi: 10.1002/humu.23770. Epub 2019 Sep 3.


The typical phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome involves three cardinal symptoms as the name describes, harboring biallelic mutations on VPS33B or VIPAS39. Except for ARC syndrome, low gamma-glutamyltransferase (GGT) cholestasis often implies hereditary hepatopathy of different severity; however, some remain undiagnosed. Several monogenic defects typically with multiorgan manifestations may only present liver dysfunction at times, such as DGUOK defect and AGL defect. Previously, four VPS33B mutated cases were reported without arthrogryposis, or with less severe symptoms and longer lifespan, indicating the possibility of incomplete ARC phenotype of isolated hepatopathy. So we retrospectively reviewed all patients with confirmed VPS33B/VIPARS39 defect in our center and identified three presenting isolated low-GGT cholestasis with intractable pruritus. Distinguished from others with typical ARC phenotype, these patients did not suffer the other two typical characteristics, survived much longer, and shared a novel missense VPS33B variation c.1726T>C, p.Cys576Arg, causing declined protein expression and abolished interaction with VIPAS39 in-vitro. Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.

Keywords: ARC; Novel; VPS33B; incomplete phenotype; isolated cholestasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency*
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Bile Acids and Salts / blood
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cholestasis, Intrahepatic / genetics*
  • Cholestasis, Intrahepatic / metabolism
  • Down-Regulation
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mutation, Missense*
  • Pedigree
  • Retrospective Studies
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B
  • Bile Acids and Salts
  • VIPAS39 protein, human
  • VPS33B protein, human
  • Vesicular Transport Proteins

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 3