Exploration of the responsible gene and the pathophysiology for unidentified fever syndromes by whole genome analysis and cell-based engineering

2014 Fiscal Year Final Research Report

• Project/Area Number: 24390263
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: NISHIKOMORI Ryuta 京都大学, 医学(系)研究科(研究院), 准教授 (70359800)
• Co-Investigator(Kenkyū-buntansha): HEIKE Toshio 京都大学, 医学研究科, 教授 (90190173) ; YASUMI Takahiro 京都大学, 医学研究科, 講師 (00511891)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu かずさDNA研究所, ヒトゲノム研究部, 部長 (20370926) ; SAITO Megumu 京都大学, iPS細胞研究所, 准教授 (90535486) ; TOGUCHIDA Junya 京都大学, 再生医科学研究所, 教授 (40273502)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 自己炎症性症候群 / 炎症 / メンデル遺伝疾患 / 全エクソーム解析 / 自然免疫 / NLRP3 / 軟骨 / 不明熱

Outline of Final Research Achievements

We implemented Massive Parallel Sequencing technology to reduce the costs　for diagnostic sequencing and to detect somatic mosaicism. We also demonstrated that NLRP3 mosaicism causes Muckle-Wells syndrome in a collaborative study with the Spanish group. To identify the responsible genes for the unidentified but suspected cases with inflammation, trio-based whole exome sequencing was performed. We identified three genes responsible for the inflammatory diseases, FLNA, IFIH1 and NLRC4.
For the delineation of pathophysiology of epiphyseal overgrowth in CINCA syndrome, we utilized iPS technology by differentiating patient-derived iPS cells into chondrocytes. The chondrocyte tissues obtained from the mutated iPS cells showed the larger sizes, increased SOX9 expression, and increased production of extracellular matrix. NLRP3 inflammasome is not contributing to the larger chondrocyte tissues. cAMP/PKA/CREB pathway is important for the SOX9 upregulation by NLRP3 mutants.

Free Research Field

自然免疫系メンデル遺伝疾患特に自己炎症性症候群