Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms.
Yasuyuki ShimaShota SasagawaNakao OtaRieko OyamaMinoru TanakaMie Kubota-SakashitaHirochika KawakamiMika KobayashiNaoko TakuboAtsuko Nakanishi OzekiXiaoning SunYeon-Jeong KimYoichiro KamataniKoichi MatsudaKazuhiro MaejimaMasashi FujitaKosumo NodaHiroyasu KamiyamaRokuya TanikawaMotoo NaganeJunji ShibaharaToru TanakaYoshiyuki RikitakeNobuko MatagaSatoru TakahashiKenjiro KosakiHideyuki OkanoTomomi FurihataRyo NakakiNobuyoshi AkimitsuYouichiro WadaToshihisa OhtsukaHiroki KuriharaHiroyuki KamiguchiShigeo OkabeMasato NakafukuTadafumi KatoHidewaki NakagawaNobuhito SaitoHirofumi NakatomiPublished in: Science translational medicine (2023)
Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes ( PDGFRB , AHNAK , OBSCN , RBM10 , CACNA1E , and OR5P3 ), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.
Keyphrases
- signaling pathway
- gene expression
- pi k akt
- subarachnoid hemorrhage
- oxidative stress
- lps induced
- induced apoptosis
- single cell
- genome wide
- cell proliferation
- dna methylation
- copy number
- epithelial mesenchymal transition
- type diabetes
- inflammatory response
- diabetic rats
- brain injury
- mesenchymal stem cells
- cancer therapy
- bioinformatics analysis
- physical activity
- late onset
- drug induced
- cystic fibrosis
- transcription factor
- metabolic syndrome
- endoplasmic reticulum stress
- cerebral ischemia
- cell therapy
- bone marrow
- escherichia coli
- high glucose
- early onset
- high fat diet induced