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Kidney Week

Abstract: SA-OR091

ALG9 Mutation Carriers Develop Kidney and Liver Cysts

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Besse, Whitney E., Yale School of Medicine, New Haven, Connecticut, United States
  • Chang, Alex R., Geisinger Clinic, Danville, Pennsylvania, United States
  • Luo, Jonathan Z., Geisinger Clinic, Danville, Pennsylvania, United States
  • Triffo, William Jeffrey, Geisinger Clinic, Danville, Pennsylvania, United States
  • Gulati, Ashima, Yale School of Medicine, New Haven, Connecticut, United States
  • Jones, Marcus, Regeneron Pharmaceuticals, Tarrytown, New York, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Mirshahi, Tooraj, Geisinger Clinic, Danville, Pennsylvania, United States
  • Somlo, Stefan, Yale School of Medicine, New Haven, Connecticut, United States

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease. Mutations in PKD1 or PKD2 cause typical ADPKD. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum (ER) whose loss results in defective production of the low abundance complex polytopic membrane protein polycystin-1 (PC1), the PKD1 gene product.


Whole exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease was used to identify a candidate gene, ALG9. This candidate was functionally validated using in vitro cell-based assays of PC1 protein maturation. For further validation, we identified carriers of ALG9 loss of function mutations (cases) and non-carrier controls matched by gender, ethnicity, age and CKD stage at time of imaging, imaging type and year, in a large exome-sequenced population-based cohort of >92,000 individuals. We assessed kidney and liver lesions in a blinded fashion using pre-specified radiographic criteria.


Two patients in the clinically-defined cohort had rare loss of function variants in ALG9. ALG9 encodes an ER protein required for addition of two mannose molecules to the lipid-linked oligosaccharide precursors for asparagine-linked glycosylation. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. We found 21 carriers of heterozygous ALG9 loss of function mutations. Eleven of these had abdominal imaging. Seven of 11 (64%) had at least 4 kidney cysts, including 7 of 8 (88%) of those over age 50, compared with none in the 22 matched controls without ALG9 mutations (P = 7.7 x 10-5, P = 2.3 x 10-5 respectively).


ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. It may be considered when clinically diagnosed ADPKD or isolated polycystic liver disease remain genetically unresolved. This study supports the utility of genotype-driven validation and analysis of candidate disease gene phenotypes in the era of precision medicine.


  • NIDDK Support