GANAB encodes the α -subunit of glucosidase II (GIIα). N -glycans with the Glc3Man9GlcNAc2 sequence, of which GANAB is a key regulator, participate in the protein folding process in the endoplasmic reticulum, where the balance between glycosylation/deglycosylation on the innermost glucose residue is regulated according to the GANAB/UGGT concentration ratio [1].

Pathogenic GANAB variants have been linked to autosomal dominant polycystic kidney and liver disease (ADPKD and ADPLD). Five novel GANAB variants associated with polycystic liver disease (PLD) in ADPKD and ADPLD patients were identified. These variants may lead to decreased or complete loss of enzymatic activity of glucosidase II [2]. However, in mice, homozygous mutation of the Ganab gene resulted in early embryonic lethality, and Ganab haploinsufficiency did not cause kidney or liver cysts, suggesting it may not be the causative gene in polycystic kidney disease [4]. In multiple sclerosis (MS) patients, GANAB was found to be downregulated in interferon-treated and responder patients. Its expression correlated with clinical parameters, making it a biomarker of neuroinflammation predictive for disease activity and treatment response in MS [3].

In summary, GANAB is crucial for the protein folding process through its role in regulating N -glycans. While GANAB variants are associated with polycystic kidney and liver diseases in humans, mouse models have provided insights into the non-causative nature of Ganab haploinsufficiency in polycystic kidney disease. In MS, GANAB shows potential as a biomarker. These findings from model-based research enhance our understanding of GANAB's functions and its implications in disease.

References:

1. De Masi, Roberto, Orlando, Stefania. 2022. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review. In International journal of molecular sciences, 23, . doi:10.3390/ijms23137373. https://pubmed.ncbi.nlm.nih.gov/35806376/

2. van de Laarschot, Liyanne F M, Te Morsche, René H M, Hoischen, Alexander, Roepman, Ronald, Drenth, Joost P H. 2020. Novel GANAB variants associated with polycystic liver disease. In Orphanet journal of rare diseases, 15, 302. doi:10.1186/s13023-020-01585-4. https://pubmed.ncbi.nlm.nih.gov/33097077/

3. De Masi, Roberto, Orlando, Stefania. 2021. GANAB as a Novel Biomarker in Multiple Sclerosis: Correlation with Neuroinflammation and IFI35. In Pharmaceuticals (Basel, Switzerland), 14, . doi:10.3390/ph14111195. https://pubmed.ncbi.nlm.nih.gov/34832977/

4. Geng, Guangrui, Xiao, Yunming, Zhang, Yingjie, Li, Qinggang, Chen, Xiangmei. 2020. Ganab Haploinsufficiency Does Not Cause Polycystic Kidney Disease or Polycystic Liver Disease in Mice. In BioMed research international, 2020, 7469428. doi:10.1155/2020/7469428. https://pubmed.ncbi.nlm.nih.gov/32550232/