Novel GANAB variants associated with polycystic liver disease
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RESEARCH
Novel GANAB variants associated with polycystic liver disease Liyanne F. M. van de Laarschot1, René H. M. te Morsche1, Alexander Hoischen2, Hanka Venselaar3, Hennie M. Roelofs1, Wybrich R. Cnossen1, Jesus M. Banales4,5,6, Ronald Roepman2† and Joost P. H. Drenth1*†
Abstract 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. Keywords: Polycystic liver disease, Glucosidase II, Molecular inversion probe analysis, Liver cysts, Cholangiocytes Background Development of numerous liver cysts is the primary phenotype of autosomal dominant polycystic liver disease (ADPLD). ADPLD patients may present with few *Correspondence: [email protected] † Ronald Roepman and Joost P. H. Drenth should be considered joint senior author 1 Department of Gastroenterology and Hepatology, Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Full list of author information is available at the end of the article
kidney cysts, but renal function remains preserved [1, 2]. On the contrary, kidney cysts are the dominant feature of patients with autosomal dominant
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