Novel GANAB variants associated with polycystic liver disease

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.

Molecular Mechanisms of Isolated Polycystic Liver Diseases

“…All mutations in the HGMD database are summarized in Figure 4. In patients diagnosed as PCLD carrying GANAB mutation, mild-to-severe PKD with absent to moderate PKD could be observed (Porath et al, 2016;Besse et al, 2017;Besse et al, 2018;van de Laarschot et al, 2020). Compared to the PCLD patients with other gene mutations, a higher frequency of PKD could be observed in these patients.…”

A SEC61A1 variant is associated with autosomal dominant polycystic liver disease

“…Interestingly, a phenotypic overlap between ADPKD and ADTKD has been described for variants in DNAJB11 , a co‐chaperone of BiP, which is involved in gating of SEC61 translocon pore 12 . Furthermore, there is a phenotypic overlap between isolated ADPLD and ADPKD, involving genes like GANAB , ALG8 and ALG9 21–24 …”

“…Especially, mutations in GANAB, ALG8 and ALG9 have been reported to cause both phenotypes, ADPKD and ADPLD. [21][22][23][24] Furthermore, partial phenotypic overlap between ADPKD and autosomal dominant tubulointerstitial kidney disease (ADTKD) has been described for patients with DNAJB11 changes. 12 Despite massive sequencing efforts a causative gene can only be identified in about 50% of cases with isolated PLD so far.…”

“…However, there is significant overlap between ADPKD and ADPLD with the same mutation that may cause both an ADPKD and an ADPLD phenotype in different individuals within the same family. Especially, mutations in GANAB , ALG8 and ALG9 have been reported to cause both phenotypes, ADPKD and ADPLD 21–24 . Furthermore, partial phenotypic overlap between ADPKD and autosomal dominant tubulointerstitial kidney disease (ADTKD) has been described for patients with DNAJB11 changes 12 .…”

A novel missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

“…Isolated polycystic liver diseases have been connected to mutations in genes including Protein Kinase C Substrate 80K-H ( PRKCSH ), SEC63 , LDL receptor Related Protein 5 ( LRP5 ), SEC61B , α-1,3-Glucosyltransferases ALG8 , and ALG9 (Besse et al, 2019; Besse et al, 2017; Cnossen et al, 2014; Davila et al, 2004; Li et al, 2003a). Mutations in Glucosidase II α Subunit ( GANAB ) cause rare cases of PLD with and without renal cysts (Porath et al, 2016; van de Laarschot et al, 2020). With the exception of LRP5 , all six genes identified in isolated PLD encode proteins that are located in the endoplasmic reticulum (ER).…”