ALG9 Mutation Carriers Develop Kidney and Liver Cysts.

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is primarily caused by mutations in PKD1 or PKD2.
• Other genes involved in endoplasmic reticulum protein biogenesis are linked to ADPKD spectrum disorders, affecting polycystin-1 (PC1) production.
• Genetic heterogeneity in ADPKD necessitates identification of novel disease-causing genes.

Purpose of the Study:

• To identify novel genes associated with genetically unresolved ADPKD and polycystic liver disease.
• To functionally validate the role of candidate genes in PC1 protein maturation.
• To establish genotype-phenotype correlations within the ADPKD spectrum.

Main Methods:

• Whole-exome sequencing was performed on 122 patients with unresolved ADPKD or polycystic liver disease.
• Candidate gene ALG9 was identified and functionally validated using in vitro cell-based assays.
• Loss-of-function mutation carriers of ALG9 and non-carrier controls were analyzed in a population-based cohort for polycystic phenotypes.

Main Results:

• Two patients harbored rare loss-of-function variants in ALG9, a gene crucial for N-glycan precursor addition.
• In vitro studies demonstrated that ALG9 inactivation impairs PC1 maturation and glycosylation.
• Eightyeight percent of ALG9 mutation carriers over 50 had at least four kidney cysts, compared to none in controls.

Conclusions:

• ALG9 is identified as a novel disease gene contributing to the genetic diversity of ADPKD.
• Phenotype characterization in genetically defined cohorts is valuable for validating new disease genes.
• This study provides essential genotype-phenotype correlations for ALG9-associated disorders.