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Kidney Week

Abstract: PO1245

Mutations to ALG5 Cause Autosomal Dominant Fibrocystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Lemoine, Hugo, INSERM UMR1078, Brest, France
  • Raud, Loann, INSERM UMR1078, Brest, France
  • Olinger, Eric Gregory, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
  • Sayer, John Andrew, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom
  • Harris, Peter C., Mayo Clinic Division of Nephrology and Hypertension, Rochester, Minnesota, United States
  • Le Meur, Yannick, CHU Brest, Brest, France
  • Audrezet, Marie-Pierre, CHU Brest, Brest, France
  • Cornec-Le Gall, Emilie, INSERM UMR1078, Brest, France

Group or Team Name

  • Genkyst Study Group
Background

Autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD1 or PKD2 encoding polycystin (PC)1 and PC2, or in genes involved in PC1 biogenesis. Seven to 10% of the pedigrees remain genetically unresolved (GUR). We hypothesized that other genes involved may cause ADPKD.

Methods

Whole exome sequencing (WES) was performed in a large GUR ADPKD-like pedigree from the Genkyst cohort, and targeted next-generation sequencing (TNGS) was performed in ~250 additional ADPKD/ADTKD GUR pedigrees.

Results

WES identified a heterozygous ALG5 frameshift variant (c.703_704delCA) in 3 sisters who developed end-stage renal disease (ESRD) at ages 62, 69, and 68 respectively and presented atrophic kidneys with small renal cysts and few to no liver cysts. Four affected relatives from three generations were subsequently identified. ALG5 encodes an endoplasmic reticulum (ER) resident enzyme, the dolichyl-phosphate beta-glucosyltransferase that catalyzes the transfer of glucose residues to the growing N-glycan precursor in the ER lumen. TNGS led to the identification of ALG5 likely pathogenic variants (p.Trp258*, p.Arg212His) in 2 additional families. Two other unrelated individuals harboring likely pathogenic variants of ALG5 were identified in the Genomics England 100,000 genomes project. The clinical phenotype was consistent in the 16 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy and few or no liver cysts; 7 subjects reached ESRD from 62 to 91y. Characterization of ALG5-/- RCTE cells showed that ALG5 is required for maturation and surface localization of PC1. PC1 surface localization in ALG5-/- cells was rescued by wild-type (WT), but not mutant, ALG5. Unfolded protein response (UPR) effector analysis revealed marked upregulation in ALG5-/- and ALG5+/- as compared to WT RCTE cells.

Conclusion

ALG5 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. Mutations to ALG5 impair PC1 maturation and localization, and are likely associated with a dysregulation of the UPR, causing renal cystogenesis and fibrosis.

Funding

  • Government Support – Non-U.S.