Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

Autor:	Karasozen Y; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Osbun JW; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Parada CA; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Busald T; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Tatman P; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Gonzalez-Cuyar LF; Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA., Hale CJ; Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA., Alcantara D; Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RH, UK., O'Driscoll M; Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RH, UK., Dobyns WB; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington 98105, USA., Murray M; Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Medicine, Division of Genetics, University of Washington School of Medicine, Seattle, Washington 98195, USA., Kim LJ; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA., Byers P; Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Medicine, Division of Genetics, University of Washington School of Medicine, Seattle, Washington 98195, USA., Dorschner MO; Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA., Ferreira M Jr; Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA. Electronic address: manuelf3@uw.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2019 May 02; Vol. 104 (5), pp. 968-976. Date of Electronic Publication: 2019 Apr 25.
DOI:	10.1016/j.ajhg.2019.03.014
Abstrakt:	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.)
Databáze:	MEDLINE
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