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

Abstract

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 gammaglutamyltransferase (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. K E Y W O R D S ARC, incomplete phenotype, isolated cholestasis, Novel, VPS33B Human Mutation. 2019;40:2247-2257.wileyonlinelibrary.com/journal/humu

A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

“…Consequently, they were unable to fulfill their mission, i.e., to excrete bile acids, conjugated bilirubin, ALP, cholesterol, and other substances to the bile ducts [ 6 , 17 , 18 ]. In accordance with experimental findings and previously reported ARC patients, our patient developed elevated serum levels of conjugated bilirubin, bile acids, ALP, and triglycerides, and mildly elevated transaminases [ 8 , 10 – 12 , 19 – 23 ]. Normal of GGT is a constant finding in ARC-associated intrahepatic cholestasis and can be explained by the presence of normal bile ducts.…”

“…The stop-codon mRNA mediated decay of these mutations, although not proven, if present, should have a similar detrimental effect. The fact that a frame shift mutation in the report by Qiu et al [ 19 ] is considered pathogenic and the affected amino acid is located 137 amino-acids downstream in the protein sequence than the affected amino acid in the current case, greatly supporting the pathogenic nature of the mutation in our patient too. Smith et al [ 33 ] reported a single patient with failure to thrive, developmental delay, sensorineural hearing loss, renal loss of protein and amino acids, bilateral talipes with osteopenia, mild cholestasis, pruritus, and ichthyosis, but no arthrogryposis.…”

“…Additional comorbidities in our patient described previously in ARC patients include severe growth faltering despite adequate energy intake, stunting, neurodevelopmental delay, hypoplastic corpus callosum, dry and scaling skin, recurrent febrile episodes with or without evidence of infection, and increased serum triglycerides [ 8 , 10 – 13 , 19 , 23 – 25 , 30 ].…”

“…They both affect the VPS 33 B gene, both are homozygous, frameshift, and chain-terminating mutations, both affect the same general protein domain (amino acid positions 376 and 324, respectively), both may result in mRNA mediated decay (not proven), and both involve deletions of a limited number of bases (two bases in our case, one base in the case of the report by Bull et al [ 23 ]). Qiu et al [ 19 ] reported two families, a total of three patients (single patient in one family and two siblings in the other) with confirmed VPS 33 B mutations who had only isolated cholestasis and no additional clinical findings, without arthrogryposis. Apparently, none of the other hallmarks of ARC syndrome were present.…”

A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

“…One ARC patient was reported with high GGT cholestasis [63]. Recently, VPS33B variants were identified in patients that presented cholestasis but no other clinical features of classic ARC [64], underscoring a strong association between VPS33B and cholestasis.…”