Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

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.

• Authors: Yigit Karasozen, Joshua W Osbun, Carolina Angelica Parada, Tina Busald, Philip Tatman, Luis F Gonzalez-Cuyar, Christopher J Hale, Diana Alcantara, Mark O'Driscoll, William B Dobyns, Mitzi Murray, Louis J Kim, Peter Byers, Michael O Dorschner, Manuel Ferreira Jr
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 104 Issue 5 Pg. 968-976 (05 02 2019) ISSN: 1537-6605 [Electronic] United States
• PMID: 31031011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• PDGFRB protein, human
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Adolescent
• Adult
• Amino Acid Sequence
• Aneurysm (genetics, pathology)
• Child
• Cohort Studies
• Female
• Humans
• Intracranial Aneurysm (genetics, pathology)
• Male
• Mutation
• Receptor, Platelet-Derived Growth Factor beta (genetics)
• Sequence Homology
• Young Adult