Novel PKD1 Mutation (c.G10086T) Drives High Intracranial Aneurysm Risk in Autosomal Dominant Polycystic Kidney Disease

Overview

Journal Eur J Neurol

Publisher Wiley

Specialty Neurology

Date 2025 Feb 20

PMID 39973757

Authors

Lili Gao

Min Lin

Chenghan Wu

Yuansheng Liao

Zuopeng Lin

Xiaohua Yan

Sheng Lin

Yinzhou Wang

Jing Chen

Zhaocong Zheng

Jushan Lin

Sheng Zhang

Jianhua Guan

Yan Qiu

Jilian Liao

Lihua Wu

Affiliations

Soon will be listed here.

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by intracranial aneurysms (IAs). However, the genetic factors driving the elevated IA risk in ADPKD remain poorly understood. In this study, we identified a novel PKD1 mutation associated with a remarkably high IA incidence in a large Chinese ADPKD family.

Methods: We conducted whole-exome sequencing in a three-generation Chinese ADPKD family (n = 24) characterized by an unusually high IA prevalence. The pathogenicity of the identified PKD1 variant was validated through comprehensive functional studies, including protein localization, calcium signaling, and endothelial cell behavior analyses.

Results: We discovered a novel PKD1 mutation (c.G10086T) that co-segregated with disease in all affected family members. Notably, 38.1% (8/21) of the mutation carriers developed IAs, a significantly higher rate than reported in general ADPKD populations (4%-11.5%). Functional studies revealed that this mutation disrupted polycystin-1 trafficking and impaired calcium signaling, leading to endothelial dysfunction. In vitro experiments demonstrated enhanced angiogenic potential and compromised vascular integrity in cells expressing mutant PKD1.

Conclusions: The newly identified PKD1:c.G10086T mutation represents a high-risk genetic variant for IA development in ADPKD. Our findings provide new insights into the vascular complications of ADPKD and suggest that PKD1 genotyping may help identify patients requiring intensive IA surveillance. This study supports the development of mutation-specific screening strategies for ADPKD-associated vascular complications.

References

Sanchis I, Shukoor S, Irazabal M, Madsen C, Chebib F, Hogan M . Presymptomatic Screening for Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol. 2019; 14(8):1151-1160. PMC: 6682820. DOI: 10.2215/CJN.14691218. View

Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X . The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nat Commun. 2023; 14(1):1790. PMC: 10063565. DOI: 10.1038/s41467-023-37449-1. View

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

Mallawaarachchi A, Hort Y, Cowley M, McCabe M, Minoche A, Dinger M . Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. Eur J Hum Genet. 2016; 24(11):1584-1590. PMC: 5110048. DOI: 10.1038/ejhg.2016.48. View

Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16):e164. PMC: 2938201. DOI: 10.1093/nar/gkq603. View

Chebib F, Torres V . Recent Advances in the Management of Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol. 2018; 13(11):1765-1776. PMC: 6237066. DOI: 10.2215/CJN.03960318. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

Porath B, Gainullin V, Cornec-Le Gall E, Dillinger E, Heyer C, Hopp K . Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet. 2016; 98(6):1193-1207. PMC: 4908191. DOI: 10.1016/j.ajhg.2016.05.004. View

Torres V, Chapman A, Devuyst O, Gansevoort R, Perrone R, Koch G . Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017; 377(20):1930-1942. DOI: 10.1056/NEJMoa1710030. View

10.

Rossetti S, Chauveau D, Kubly V, Slezak J, Saggar-Malik A, Pei Y . Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet. 2003; 361(9376):2196-201. DOI: 10.1016/S0140-6736(03)13773-7. View

11.

Thompson B, Brown Jr R, Amin-Hanjani S, Broderick J, Cockroft K, Connolly Jr E . Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015; 46(8):2368-400. DOI: 10.1161/STR.0000000000000070. View

12.

Harris P, Torres V . Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. J Clin Invest. 2014; 124(6):2315-24. PMC: 4089452. DOI: 10.1172/JCI72272. View

13.

Heyer C, Sundsbak J, Abebe K, Chapman A, Torres V, Grantham J . Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2016; 27(9):2872-84. PMC: 5004648. DOI: 10.1681/ASN.2015050583. View

14.

Gainullin V, Hopp K, Ward C, Hommerding C, Harris P . Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner. J Clin Invest. 2015; 125(2):607-20. PMC: 4350419. DOI: 10.1172/JCI76972. View

15.

Pei Y, Obaji J, Dupuis A, Paterson A, Magistroni R, Dicks E . Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2008; 20(1):205-12. PMC: 2615723. DOI: 10.1681/ASN.2008050507. View

16.

Chapman A, Devuyst O, Eckardt K, Gansevoort R, Harris T, Horie S . Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2015; 88(1):17-27. PMC: 4913350. DOI: 10.1038/ki.2015.59. View

17.

. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell. 1994; 77(6):881-94. DOI: 10.1016/0092-8674(94)90137-6. View

18.

Griffin M, Torres V, Grande J, Kumar R . Vascular expression of polycystin. J Am Soc Nephrol. 1997; 8(4):616-26. DOI: 10.1681/ASN.V84616. View

19.

Mahmood T, Yang P . Western blot: technique, theory, and trouble shooting. N Am J Med Sci. 2012; 4(9):429-34. PMC: 3456489. DOI: 10.4103/1947-2714.100998. View

20.

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View