Establishment of a method for functional analysis of CARD9 mutations

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15904
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Hiroshima University
• Principal Investigator: Kagawa Reiko 広島大学, 病院(医), 助教 (40806634)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: CARD7 / IL-6 / IL-8 / TNF / NF-kB

Outline of Final Research Achievements

CARD9 deficiency is a disease caused by loss-of-function mutations in the CARD9 gene that results in severe fungal infections. Genetic testing is the mainstay for diagnosis of this disease, and novel mutations must be evaluated for pathological significance. We identified the first patient in Japan with this disease and a novel mutation. The pathological significance of the novel mutations was evaluated in this study. We showed that the production of IL-6, IL-8, and TNF upon fungal stimulation was decreased in monocytes from patients and asymptomatic patients with compound heterozygous mutations. On the other hand, we introduced the mutation into HEK293 cells and evaluated IL-8 production and NF-KB activity after fungal stimulation, but did not obtain useful results. Even in asymptomatic patients, a decrease in cytokine production such as IL-6, IL-8, and TNF can be considered a risk factor for fungal infection.

Free Research Field

免疫

Academic Significance and Societal Importance of the Research Achievements

本疾患は重篤な真菌感染症を合併する可能性があり、本症を疑われれば迅速かつ正確な診断が必要である。また、本疾患の責任遺伝子であるCARD7遺伝子に病的変異を複合ヘテロ接合性に有していても、無症状患者が存在することもある。本研究では、新規CARD7変異を同定しその病的意義の評価を行なった。無症状患者においても、真菌刺激に対するI L-6 , I L-8 ,TNFの産生低下が認められ真菌感染症のリスクを保因していることを示した。一方でin vitroでの実験系は確立できなかったが、新規変異が同定された場合には、真菌刺激に対するサイトカイン産生を評価することで発症リスクが判断可能となる。