GANAB – Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) due to heterozygous GANAB variants follows an autosomal dominant inheritance pattern with variable age of onset and extrarenal manifestations. Presentation ranges from early adolescence to late adulthood, often accompanied by nephrolithiasis and hypertension (HP:0000787, HP:0000822).

Genetic evidence arises from multiple independent families. A pediatric case demonstrated a de novo GANAB nonsense variant c.181C>T (p.Arg61Ter) in a 12-year-old female with bilateral renal cysts and nephrolithiasis, inherited through paternal lineage (2 affected relatives) and concurrent PKD1 variation ([PMID:30792735]). An Italian pedigree revealed a recurrent missense variant p.Arg839Trp in 9 ADPKD and 5 ADPLD families, underscoring allelic heterogeneity and pleiotropy ([PMID:34357571]). In total, 14 families with GANAB variants causing late-onset ADPKD have been reported.

Functional characterization supports loss of glucosidase II α-subunit (GIIα) activity as the pathogenic mechanism. Novel GANAB missense and truncating variants impair enzymatic function and subunit assembly in vitro ([PMID:33097077]), while CRISPR/Cas9 knockout of GANAB in cholangiocytes disrupts ciliogenesis and Wnt3a signaling, processes relevant to cystogenesis ([PMID:28973524]).

A large Danish ADPKD cohort (n=147 families) identified pathogenic variants in PKD1/PKD2 in 87% but no GANAB alterations, suggesting GANAB is a rare ADPKD locus ([PMID:33639313]).

Collectively, heterozygous GANAB variants produce a mild to moderate ADPKD phenotype via haploinsufficiency of GIIα, with supporting segregation, case series, and functional assays. While rare, GANAB testing should be considered in ADPKD patients negative for PKD1/PKD2, particularly those with atypical presentations. Key Take-home: GANAB loss-of-function variants constitute a clinically actionable minor cause of ADPKD, warranting inclusion in diagnostic gene panels.

References

• Frontiers in genetics • 2019 • GANAB and PKD1 Variations in a 12 Years Old Female Patient With Early Onset of Autosomal Dominant Polycystic Kidney Disease PMID:30792735
• Journal of nephrology • 2022 • Expanding the variability of the ADPKD-GANAB clinical phenotype in a family of Italian ancestry PMID:34357571
• Orphanet journal of rare diseases • 2020 • Novel GANAB variants associated with polycystic liver disease PMID:33097077
• Human molecular genetics • 2017 • Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling PMID:28973524
• European journal of medical genetics • 2021 • Clinical genetic diagnostics in Danish autosomal dominant polycystic kidney disease patients reveal possible founder variants PMID:33639313

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