A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis
Elhussein A. Elhassan, Tereza Kmochová, Katherine A. Benson, Neil K. Fennelly, Veronika Barešová, Kendrah Kidd, Brendan Doyle, Anthony Dorman, Martina Morrin, Niamh C. Kyne, Petr Vyleťal, Hana Hartmannová, Kateřina Hodaňová, Jana Sovová, Dita Mušálková, Alena Vrbacká, Anna Přistoupilová, J Živný, Klára Svojšová, Martin Radina, Viktor Stránecký, Dmitry S. Loginov, Petr Pompach, Petr Novák, Zdislava Vaníčková, Hana Hansíková, Silvie Rajnochová-Bloudíčková, Ondřej Viklický, Helena Hůlková, Gianpiero L. Cavalleri, Aleš Hnı́zda, Anthony J. Bleyer, Stanislav Kmoch, Peter J. Conlon, Martina Živná
Abstract
Introduction: gene encoding asparagine-linked glycosylation protein 5 homolog (ALG5) have been recently shown to disrupt polycystin-1 (PC1) maturation and trafficking via underglycosylation, causing an autosomal dominant polycystic kidney disease-like (ADPKD-like) phenotype and interstitial fibrosis. In this report, we present clinical, genetic, histopathologic, and protein structure and functional correlates of a new ALG5 variant, p.R79W, that we identified in 2 distant genetically related Irish families displaying an atypical late-onset ADPKD phenotype combined with tubulointerstitial damage. Methods: Whole exome and targeted sequencing were used for segregation analysis of available relatives. This was followed by immunohistochemistry examinations of kidney biopsies, and targeted (UMOD, MUC1) and untargeted plasma proteome and N-glycomic studies. Results: variant [GRCh37 (NM_013338.5): g.37569565G>A, c.235C>T; p.R79W] that cosegregates in 23 individuals, of whom 18 were clinically affected. We detected abnormal localization of ALG5 in the Golgi apparatus of renal tubular cells in patients' kidney specimens. Further, we detected the pathological accumulation of uromodulin, an N-glycosylated glycosylphosphatidylinositol (GPI)-anchored protein, in the endoplasmic reticulum (ER), but not mucin-1, an O- and N-glycosylated protein. Biochemical investigation revealed decreased plasma and urinary uromodulin levels in clinically affected individuals. Proteomic and glycoproteomic profiling revealed the dysregulation of chronic kidney disease (CKD)-associated proteins. Conclusion: .