A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis.
Autor: | Elhassan EAE; Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.; Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Kmochová T; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Benson KA; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin, Ireland., Fennelly NK; Department of Pathology, Beaumont Hospital, Dublin, Ireland., Barešová V; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Kidd K; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Doyle B; Department of Pathology, Beaumont Hospital, Dublin, Ireland., Dorman A; Department of Pathology, Beaumont Hospital, Dublin, Ireland., Morrin MM; Department of Radiology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland., Kyne NC; Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland., Vyleťal P; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Hartmannová H; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Hodaňová K; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Sovová J; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Mušálková D; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Vrbacká A; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Přistoupilová A; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Živný J; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Svojšová K; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Radina M; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Stránecký V; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Loginov D; Institute of Microbiology, The Czech Academy of Sciences, Vestec, Czech Republic., Pompach P; Institute of Microbiology, The Czech Academy of Sciences, Vestec, Czech Republic., Novák P; Institute of Microbiology, The Czech Academy of Sciences, Vestec, Czech Republic., Vaníčková Z; Institute of Medical Biochemistry and Laboratory Diagnostics of the General University Hospital and of The First Faculty of medicine of Charles University in Prague, Prague, Czech Republic., Hansíková H; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Rajnochová-Bloudíčková S; Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Viklický O; Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic., Hůlková H; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Cavalleri GL; School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons, Dublin, Ireland., Hnízda A; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic., Bleyer AJ; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Kmoch S; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Conlon PJ; Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.; Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland., Živná M; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.; Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. |
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Jazyk: | angličtina |
Zdroj: | Kidney international reports [Kidney Int Rep] 2024 Apr 15; Vol. 9 (7), pp. 2209-2226. Date of Electronic Publication: 2024 Apr 15 (Print Publication: 2024). |
DOI: | 10.1016/j.ekir.2024.04.031 |
Abstrakt: | Introduction: Monoallelic variants in the ALG5 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: We identified a monoallelic ALG5 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: ALG5 dysfunction adversely affects maturation and trafficking of N-glycosylated and GPI anchored protein uromodulin, leading to structural and functional changes in the kidney. Our findings confirm ALG5 as a cause of late-onset ADPKD and provide additional insight into the molecular mechanisms of ADPKD- ALG5 . (© 2024 International Society of Nephrology. Published by Elsevier Inc.) |
Databáze: | MEDLINE |
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