ArticleBrain pathology (Zurich, Switzerland)2018
Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke.
Article in Brain pathology (Zurich, Switzerland), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- ABCC6 in Cellular Metabolic Homeostasis: Biochemical Links to Extracellular Nucleotide Signaling, Mitochondrial Stress, and Senescence.Cell biochemistry and biophysics · 2026Review
- Whole-exome sequencing identifies matrisomal gene associations in monogenic cerebral small vessel disease.Journal of neurology · 2026Article
- Severe Hypertension and Hematologic Abnormalities in Pseudoxanthoma Elasticum: A Pediatric Case Report.Journal of clinical hypertension (Greenwich, Conn.) · 2026Article
- Observational
- ABCC6 pathogenic variants are associated with hemorrhagic phenotypes in Japanese patients with severe cerebral small vessel disease.Scientific reports · 2026Article
- Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis.Orphanet journal of rare diseases · 2025Review
- ABCC6 Involvement in Cerebral Small Vessel Disease: Potential Mechanisms and Associations.Genes · 2025Review
- Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants.Journal of neurology · 2023Article
- Inorganic Pyrophosphate Plasma Levels Are Decreased in Pseudoxanthoma Elasticum Patients and Heterozygous Carriers but Do Not Correlate with the Genotype or Phenotype.Journal of clinical medicine · 2023Article
- Investigation of shared genes and regulatory mechanisms associated with coronavirus disease 2019 and ischemic stroke.Frontiers in neurology · 2023Article
- High frequency ofJournal of neurology, neurosurgery, and psychiatry · 2023Article
- The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.Human mutation · 2022Article
- A Novel Idiopathic Atrial Calcification: Pathologic Manifestations and Potential Mechanism.Frontiers in cardiovascular medicine · 2022Article
- Plasma Inorganic Pyrophosphate Deficiency Links Multiparity to Cardiovascular Disease Risk.Frontiers in cell and developmental biology · 2020Article
- Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications.International journal of molecular sciences · 2019Review
- The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders.International journal of molecular sciences · 2019Review
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
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 cryptogenic ischemic stroke.
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