A Novel Monoallelic ALG5 Variant Causing Late-Onset ADPKD and Tubulointerstitial Fibrosis

被引:3
作者
Elhassan, Elhussein A. E. [1 ,2 ]
Kmochova, Tereza [3 ]
Benson, Katherine A. [4 ]
Fennelly, Neil K. [5 ]
Baresova, Veronika [3 ]
Kidd, Kendrah [3 ,6 ]
Doyle, Brendan [5 ]
Dorman, Anthony [5 ]
Morrin, Martina M. [7 ,8 ]
Kyne, Niamh C. [1 ]
Vyletal, Petr [3 ]
Hartmannova, Hana [3 ]
Hodanova, Katerina [3 ]
Sovova, Jana [3 ]
Musalkova, Dita [3 ]
Vrbacka, Alena [3 ]
Pristoupilova, Anna [3 ]
Zivny, Jan [3 ]
Svojsova, Klara [3 ]
Radina, Martin [3 ]
Stranecky, Viktor [3 ]
Loginov, Dmitry
Pompach, Petr
Novak, Petr [9 ]
Vanickova, Zdislava [10 ,11 ]
Hansikova, Hana [12 ]
Rajnochova-Bloudickova, Silvie [13 ]
Viklicky, Ondrej [13 ]
Hulkova, Helena [3 ]
Cavalleri, Gianpiero L.
Hnizda, Ales [3 ]
Bleyer, Anthony J. [3 ,6 ]
Kmoch, Stanislav [3 ,6 ]
Conlon, Peter J. [1 ,2 ]
Zivna, Martina [3 ,6 ]
机构
[1] Beaumont Hosp, Dept Nephrol & Transplantat, Dublin, Ireland
[2] Royal Coll Surgeons Ireland, Dept Med, Dublin, Ireland
[3] Charles Univ Prague, Fac Med 1, Dept Pediat & Inherited Metab Disorders, Res Unit Rare Dis, Prague, Czech Republic
[4] Royal Coll Surg, Sch Pharm & Biomol Sci, Dublin, Ireland
[5] Beaumont Hosp, Dept Pathol, Dublin, Ireland
[6] Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC USA
[7] Beaumont Hosp, Dept Radiol, Dublin, Ireland
[8] Royal Coll Surgeons Ireland, Dublin, Ireland
[9] Czech Acad Sci, Inst Microbiol, Vestec, Czech Republic
[10] Charles Univ Prague, Gen Univ Hosp, Inst Med Biochem & Lab Diagnost, Prague, Czech Republic
[11] Charles Univ Prague, Fac Med 1, Prague, Czech Republic
[12] Charles Univ Prague, Fac Med 1, Dept Pediat & Inherited Metab Disorders, Prague, Czech Republic
[13] Inst Clin & Expt Med, Transplant Ctr, Dept Nephrol, Prague, Czech Republic
关键词
ALG5; autosomal-dominant polycystic kidney disease; autosomal dominant tubulo-interstitial kidney disease; Golgi apparatus; N-Linked protein glycosylation; UMOD; DOMINANT POLYCYSTIC KIDNEY; MUTATIONS; COLOCALIZATION;
D O I
10.1016/j.ekir.2024.04.031
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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 .
引用
收藏
页码:2209 / 2226
页数:18
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