Defects in histone modification cause phenotypic diversity of congenital malformations

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08270
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kanagawa Children's Medical Center (Clinical Research Institute)
• Principal Investigator: Kurosawa Kenji 地方独立行政法人神奈川県立病院機構神奈川県立こども医療センター(臨床研究所), 臨床研究所, 臨床研究所長 (20277031)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: ヒストン / エピゲノム / 先天異常 / クロマチン / 次世代シーケンサー

Outline of Final Research Achievements

We studied histone modification defects to uncover the mechanisms behind diverse congenital malformation syndromes. We have identified a novel variant in the atypical region associated with Say-Barber-Biesecker-Young-Simpson syndrome, which has led to the development of autism spectrum disorder. Through our investigation of a microdeletion involving the SET gene, which encodes the SET nuclear proto-oncogene, we have identified a new cranial formation phenotype. Additionally, we have established a link between the phenotype and genotype in Rubinstein-Taybi syndrome caused by the acetyltransferase CREBBP. These findings suggest that the various clinical symptoms resulting from abnormalities in histone modifications stem not only from different genetic variations but also from the diverse functions of individual histone modifiers by domain. Further analysis is needed to explore potential therapeutic approaches.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

先天異常症候群において、ヒストン修飾因子およびその関連因子の異常を原因とする疾患は少なくない。多くは、根本治療は困難で対症療法が中心となる。治療への手がかりとして発症メカニズムの解明は重要である。今回の研究により、表現型（臨床像）の多様性が変異の多様性に由来し、同じ因子であっても変異の種類によって発症機構が大きく異なることを明らかにできた。このことは、社会的には患者家族に疾患理解を促すこととなり、学術的には治療法開発の手がかりとなりえる。