ALG5 – Autosomal Dominant Polycystic Kidney Disease

ALG5 has emerged as a gene associated with the autosomal dominant polycystic kidney disease (ADPKD) spectrum. Multiple independent studies have identified monoallelic variants in ALG5 in families with kidney cysts and progressive renal dysfunction (PMID:35896117, PMID:39081747). Genetic analysis across several cohorts has revealed that affected individuals harbor frameshift and missense variants that compromise ALG5 function, leading to abnormal N-linked glycosylation and disrupted polycystin‑1 (PC1) maturation. The consistency of the phenotypes across unrelated families provides important clinical evidence for this gene‑disease association.

Clinical findings indicate that carriers of pathogenic ALG5 variants typically exhibit multiple small kidney cysts, non‐enlarged kidneys, and progressive interstitial fibrosis. In one large multi‑patient analysis, a monoallelic frameshift variant, c.703_704del (p.Gln235ValfsTer21), was identified in 23 affected individuals across different families (PMID:35896117). Segregation analysis further reinforces the association as the variant cosegregates with kidney disease in extended pedigrees. Moreover, the affected subjects display a milder renal phenotype compared to classical PKD1‑related ADPKD, suggesting a distinct mechanistic contribution by ALG5 haploinsufficiency.

The inheritance pattern observed in these studies is autosomal dominant. The genetic evidence is strengthened by the fact that multiple unrelated probands and their relatives display clear segregation of the ALG5 variant with the disease phenotype. Detailed case series and targeted sequencing studies have confirmed that the presence of pathogenic ALG5 alleles accounts for a subset of ADPKD cases that were previously genetically unresolved (PMID:39881088).

Functional studies have provided additional insights into the disease mechanism. Experimental evidence shows that ALG5 haploinsufficiency disrupts the normal synthesis of N‑glycan chains in renal epithelial cells, thereby impairing PC1 maturation, its localization in the membrane and primary cilia, and ultimately triggering cyst formation and interstitial fibrosis (PMID:10359825, PMID:18403407). Furthermore, cellular models and histopathologic assessments have confirmed that the perturbation in glycosylation is directly related to the clinical phenotype seen in patient kidney biopsies.

Collectively, the clinical and genetic data converge to support a strong association between ALG5 and ADPKD. Although additional studies may further elucidate the complete spectrum of phenotypic variation, current evidence—including segregation in 23 affected subjects and compelling functional assays—strongly validates the role of monoallelic ALG5 variants in this kidney disease (PMID:39081747).

No significant conflicting evidence has been reported to dispute the pathogenic role of ALG5 in ADPKD. Instead, the data from multi‑patient cohorts and diverse functional studies complement each other, providing a robust framework for diagnostic interpretation and clinical decision‑making.

In summary, the integration of genetic and experimental findings confirms that monoallelic ALG5 variants contribute to an atypical ADPKD phenotype marked by cystic kidney changes and fibrosis. This gene‑disease association is of high clinical utility, guiding genetic testing and informing patient management decisions.

References

• American Journal of Human Genetics • 2022 • Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis PMID:35896117
• Kidney International Reports • 2024 • A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis PMID:39081747
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic PMID:10359825
• Development (Cambridge, England) • 2008 • Wollknauel is required for embryo patterning and encodes the Drosophila ALG5 UDP-glucose:dolichyl-phosphate glucosyltransferase PMID:18403407
• Irish Kidney Gene Project • 202? • Study on ADPKD progression and non‑PKD1 genetic variants PMID:39881088

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