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Background  Polycystic liver disease (PLD) is an inherited disorder characterized by numerous cysts in the liver. Autosomal dominant polycystic kidney and liver disease (ADPKD and ADPLD, respectively) have been linked to pathogenic  GANAB  variants.  GANAB  encodes the α-subunit of glucosidase II (GIIα). Here, we report the identification of novel  GANAB  variants in an international cohort of patients with the primary phenotype of PLD using molecular inversion probe analysis.    Results  Five novel  GANAB  variants were identified in a cohort of 625 patients with ADPKD or ADPLD. In silico analysis revealed that these variants are likely to affect functionally important domains of glucosidase II α-subunit. Missense variant c.1835G>C p.(Arg612Pro) was predicted to disrupt the structure of the active site of the protein, likely reducing its activity. Frameshift variant c.687delT p.(Asp229Glufs*60) introduces a premature termination codon predicted to have no activity. Two nonsense variants (c.2509C>T; p.(Arg837*), and c.2656C>T; p.(Arg886*)) and splice variant c.2002+1G>C, which causes aberrant pre-mRNA splicing and affecting RNA processing, result in truncated proteins and are predicted to cause abnormal binding of α- and β-subunits of glucosidase II, thus affecting its enzymatic activity. Analysis of glucosidase II subunits in cell lines shows expression of a truncated GIIα protein in cells with c.687delT, c.2509C>T, c.2656C>T, and c.2002+1G>C variants. Incomplete colocalization of the subunits was present in cells with c.687delT or c.2002+1G>C variants. Other variants showed normal distribution of GIIα protein.    Conclusions  We identified five novel  GANAB  variants associated with PLD in both ADPKD and ADPLD patients supporting a common pathway in cystogenesis. These variants may lead to decreased or complete loss of enzymatic activity of glucosidase II which makes  GANAB  a candidate gene to be screened in patients with an unknown genetic background.

Novel GANAB variants associated with polycystic liver disease