1. Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.
- Author
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Karasozen Y, Osbun JW, Parada CA, Busald T, Tatman P, Gonzalez-Cuyar LF, Hale CJ, Alcantara D, O'Driscoll M, Dobyns WB, Murray M, Kim LJ, Byers P, Dorschner MO, and Ferreira M Jr
- Subjects
- Adolescent, Adult, Amino Acid Sequence, Aneurysm pathology, Child, Cohort Studies, Female, Humans, Intracranial Aneurysm pathology, Male, Sequence Homology, Young Adult, Aneurysm genetics, Intracranial Aneurysm genetics, Mutation, Receptor, Platelet-Derived Growth Factor beta genetics
- Abstract
The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors., (Published by Elsevier Inc.)
- Published
- 2019
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