A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Monoallelic variants in the ALG5 gene cause an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype.
• ALG5 dysfunction leads to underglycosylation, disrupting polycystin-1 (PC1) maturation and trafficking.
• A novel ALG5 variant, p.R79W, was identified in families with atypical late-onset ADPKD and tubulointerstitial damage.

Purpose of the Study:

• To investigate the clinical, genetic, and molecular correlates of a novel ALG5 variant (p.R79W) in two Irish families with late-onset ADPKD.
• To elucidate the pathogenic mechanisms underlying ALG5-associated kidney disease.
• To explore the impact of ALG5 variants on protein glycosylation and trafficking in ADPKD.

Main Methods:

• Whole exome and targeted sequencing for genetic segregation analysis.
• Immunohistochemistry of kidney biopsies to assess protein localization.
• Plasma and urinary proteomic and N-glycomic studies, including targeted analysis of UMOD and MUC1.

Main Results:

• A monoallelic ALG5 variant (p.R79W) cosegregated with the disease in 23 individuals (18 affected).
• Abnormal ALG5 localization in the Golgi and pathological accumulation of uromodulin in the ER were observed in patient kidney cells.
• Decreased plasma and urinary uromodulin levels and dysregulation of CKD-associated proteins were detected in affected individuals.

Conclusions:

• ALG5 dysfunction impairs maturation and trafficking of N-glycosylated and GPI-anchored proteins, notably uromodulin.
• This leads to structural and functional kidney changes, confirming ALG5 as a cause of late-onset ADPKD.
• The study provides deeper insight into the molecular mechanisms of ADPKD associated with ALG5 variants.