Affordable Access

Publisher Website

Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke

  • De Vilder, Eva Y.G.1, 2, 3
  • Cardoen, Stefanie4
  • Hosen, Mohammad J.5
  • Saux, Olivier Le6
  • De Zaeytijd, Julie2
  • Leroy, Bart P.1, 2, 7
  • De Reuck, Jacques4
  • Coucke, Paul J.1
  • De Paepe, Anne1
  • Hemelsoet, Dimitri4
  • Vanakker, Olivier M.1
  • 1 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • 2 Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
  • 3 Research Foundation – Flanders, Brussels, Belgium.
  • 4 Department of Neurology, Ghent University Hospital, Ghent, Belgium.
  • 5 Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh.
  • 6 Department of Cell and Molecular Biology, The John A. Burns School of Medicine, University of Hawai’i, Honolulu, HI.
  • 7 Division of Ophthalmology, The Children’s Hospital of Philadelphia, Philadelphia, PA.
Published Article
Brain Pathology
Wiley (Blackwell Publishing)
Publication Date
Nov 01, 2018
DOI: 10.1111/bpa.12620
PMID: 29722917
PMCID: PMC6581194
PubMed Central


Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent ( P = 0.036; 95% CI 1.11–21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6 -deficient mice and wild-type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6 –/– mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfβ (Eng) signaling in the brain of Abcc6– / – mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryp togenic ischemic stroke.

Report this publication


Seen <100 times