Alternative titles; symbols
HGNC Approved Gene Symbol: GANAB
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38): 11:62,624,829-62,646,613 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.3 | Polycystic kidney disease 3 | 600666 | Autosomal dominant | 3 |
The GANAB gene encodes the catalytic alpha subunit of glucosidase II. The noncatalytic beta subunit is encoded by the PRKCSH gene (177060). Glucosidase II is an endoplasmic reticulum-resident enzyme that catalyzes the hydrolysis of glucose residues of peptide-bound oligosaccharides; it also triggers quality-control assessment of glycoprotein folding (summary by Porath et al., 2016).
Human tissues contain 2 isozymes of neutral alpha-glucosidase designated AB (GANAB) and C (GANC; 104180). Initially distinguished on the basis of differences in electrophoretic mobility in starch gel, the two have been shown to have other differences including those of substrate specificity. Since the AB form of mouse is not different electrophoretically from that in man, Martiniuk et al. (1982, 1983) used rocket immunoelectrophoresis to distinguish the enzymes from the 2 species.
Trombetta et al. (1996) isolated enzymatically active glucosidase II from rat liver and found that it was composed of 2 subunits, alpha and beta (177060). Based on peptide sequences of the purified enzyme, they identified the corresponding human cDNAs in existing sequence databases. Trombetta et al. (1996) reported that the available sequence of the alpha subunit of human glucosidase II predicts a 912-amino acid polypeptide with homology to the catalytic domains of several other glucosidases, but without significant homology to human glucosidase I. They found that the alpha subunit of human glucosidase II is a functional homolog of a gene found on S. cerevisiae chromosome II.
The GANAB gene has 2 isoforms: isoform 3 has 966 amino acids, 25 exons, and a molecular mass of about 110 kD, whereas isoform 2 has 944 amino acids, 24 exons, with an in-frame skipping of exon 6, and a molecular mass of about 107 kD. Both isoforms are approximately equally expressed in the human kidney and liver (summary by Porath et al., 2016).
Martiniuk et al. (1982, 1983) assigned the GANAB gene to 11q13-qter by study of mouse-man hybrid cells.
In 20 affected members of 9 unrelated families with polycystic kidney disease-3 with or without polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified 8 different heterozygous mutations in the GANAB gene (see, e.g., 104160.0001-104160.0006). Five of the mutations were predicted to result in a truncated protein (frameshift, nonsense, or splicing), and 3 were missense mutations. The mutation in the first family was found by whole-exome sequencing of 6 families with polycystic kidney disease (PKD); subsequent mutations were identified by Sanger sequencing of the GANAB gene in 321 families with PKD and/or polycystic liver disease (PCLD). Seven of the 9 families with GANAB mutations were diagnosed with PKD, but most of the patients also had liver cysts. The remaining 2 families were diagnosed with PCLD, and both contained at least 1 affected family member with renal cysts. Porath et al. (2016) concluded that PKD and PCLD should not be considered strictly separate diseases. Complete knockdown of GANAB in human renal cells resulted in absence of the mature N-terminal polycystin-1 (PKD1; 601313), but full-length PKD1 and polycystin-2 (PKD2; 173910) were present, indicating that GANAB plays a major role in the maturation of these proteins. Ciliary localization of PKD2 was absent in these GANAB-null cells, although cilia formed normally. Heterozygous-null GANAB renal cells had a 50% depletion of mature N-terminal PKD1. Transfection of the 3 missense mutations into GANAB-null renal cells failed to rescue the lack of surface PKD1 expression, indicating that these mutations resulted in a loss of enzyme function. The authors noted that PRKCSH, mutations in which cause polycystic liver disease-1 (PCLD1; 174050) without renal cysts, and GANAB are subunits of the same protein, so it is not clear why GANAB mutations result in more renal disease. The highly variable phenotype in these families was typical of polycystic kidney and liver disease, and allelic effects did not appear to explain this variability. The cystogenesis is most likely driven by defects in maturation of PKD1, mutations in which cause autosomal dominant polycystic kidney disease-1 (173900).
In an adult father and daughter (family M263) with polycystic kidney disease-3 with polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a heterozygous c.1265G-T transversion (c.1265G-T, NM_198335.3) in exon 12 of the GANAB gene, resulting in an arg422-to-leu (R422L) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the ExAC database and segregated with the disorder in the family. Transfection of the mutation into GANAB-null renal cells failed to rescue the lack of surface PKD1 (601313) expression, indicating that the mutation resulted in a loss of enzyme function.
In 4 members of 2 unrelated families (M641 and 290100) with polycystic kidney disease-3 with or without polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a heterozygous 2-bp deletion (c.1914_1915delAG, NM_198335.3) in the GANAB gene, resulting in a frameshift and premature termination (Asp640GlnfsTer77). The mutation, which was found by Sanger sequencing of the GANAB gene, was not found in the ExAC or Exome Variant Server databases.
In 3 members of a 3-generation family (P1174) with polycystic kidney disease-3 without polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a heterozygous c.1214C-G transversion (c.1214C-G, NM_198335.3) in exon 11 of the GANAB gene, resulting in a thr405-to-arg (T405R) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing of the GANAB gene, was not found in the ExAC or Exome Variant Server databases. Transfection of the mutation into GANAB-null renal cells failed to rescue the lack of surface PKD1 (601313) expression, indicating that the mutation resulted in a loss of enzyme function. One of the patients had 1 liver cyst.
In 4 members of a family (M656) with polycystic kidney disease-3 with polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a homozygous 6-bp deletion in intron 23 of the GANAB gene (c.2690+2_+7del, NM_198335.3), resulting in a splice site mutation. The mutation, which was found by Sanger sequencing of the GANAB gene, was not found in the ExAC or Exome Variant Server databases.
In 3 members of a family (P1073) with polycystic kidney disease-3 with polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a heterozygous c.2515C-T transition (c.2515C-T, NM_198335.3) in the GANAB gene, resulting in an arg839-to-trp (R839W) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing of the GANAB gene, was not found in the ExAC or Exome Variant Server databases. Transfection of the mutation into GANAB-null renal cells failed to rescue the lack of surface PKD1 (601313) expression, indicating that the mutation resulted in a loss of enzyme function. All 3 patients also had liver cysts; one patient's liver disease was so severe that she required a liver transplant.
In a 58-year-old woman (family M472) with polycystic kidney disease-3 with polycystic liver disease (PKD3; 600666), Porath et al. (2016) identified a heterozygous 2-bp deletion (c.152_153GA, NM_198335.3) in the GANAB gene, resulting in a frameshift and premature termination (Arg51LysfsTer21). The mutation, which was found by Sanger sequencing of the GANAB gene, was found once (1 in 60,706 unrelated individuals) in the ExAC database, but not in the Exome Variant Server database. The patient had severe polycystic liver disease, requiring surgical intervention. Her sister had a similar disorder, but genetic studies were not performed.
In 5 sibs (family T90) with polycystic kidney disease-3 with polycystic liver disease (PKD3; 600666) manifest as isolated polycystic liver disease, Besse et al. (2018) identified a heterozygous 9-bp deletion in the vicinity of the splice donor site of exon 24 of the GANAB gene (c.2791+4_2791+12del, NM_198335.3). The mutation was found by a combination of linkage analysis and direct sequencing after whole-exome sequencing did not yield results; it was confirmed by Sanger sequencing and segregated with the disorder in the family. The deletion was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. A minigene assay showed that the deletion resulted in the skipping of exon 24, a frameshift, and premature termination in cell lines and primary human cholangiocytes.
Besse, W., Choi, J., Ahram, D., Mane, S., Sanna-Cherchi, S., Torres, V., Somlo, S. A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family. Hum. Mutat. 39: 378-382, 2018. [PubMed: 29243290] [Full Text: https://doi.org/10.1002/humu.23383]
Martiniuk, F., Smith, M., Desnick, R., Astrin, K., Mitra, J., Hirschhorn, R. Assignment of the gene for neutral alpha-glucosidase AB to chromosome 11. (Abstract) Am. J. Hum. Genet. 34: 173A only, 1982.
Martiniuk, F., Smith, M., Ellenbogen, A., Desnick, R. J., Astrin, K., Mitra, J., Hirschhorn, R. Assignment of the gene for neutral alpha-glucosidase AB to chromosome 11. Cytogenet. Cell Genet. 35: 110-116, 1983. [PubMed: 6342981] [Full Text: https://doi.org/10.1159/000131851]
Porath, B., Gainullin, V. G., Cornec-Le Gall, E., Dillinger, E. K., Heyer, C. M., Hopp, K., Edwards, M. E., Madsen, C. D., Mauritz, S. R., Banks, C. J., Baheti, S., Reddy, B., and 16 others. Mutations in GANAB, encoding the glucosidase II-alpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am. J. Hum. Genet. 98: 1193-1207, 2016. [PubMed: 27259053] [Full Text: https://doi.org/10.1016/j.ajhg.2016.05.004]
Trombetta, E. S., Simons, J. F., Helenius, A. Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit. J. Biol. Chem. 271: 27509-27516, 1996. [PubMed: 8910335] [Full Text: https://doi.org/10.1074/jbc.271.44.27509]