Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum

• Published in: Genes Vol. 14; no. 8; p. 1652
• Main Authors: Boerrigter, Melissa M, Te Morsche, René H M, Venselaar, Hanka, Pastoors, Nikki, Geerts, Anja M, Hoorens, Anne, Drenth, Joost P H
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-08-2023; MDPI
• Subjects: Biobanks; Cysts; Genes; Genomes; Genomics; Genotypes; Glucosyltransferase; Homology; Humans; Kidney diseases; Kinases; Liver diseases; Liver Diseases - genetics; Phenotypes; Polycystic Kidney Diseases; Proteins; Renal function; Risk factors; Germany; United States > US; ADPLD; ALG8; polycystic liver disease; clinical spectrum; next-generation sequencing
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes14081652

Protein-truncating variants in α-1,3-glucosyltransferase (
) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic
variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic
variant carriers, we performed targeted
screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in
were discovered in sixteen patients. The
clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of <5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells.
-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype-phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.