The analysis of X chromosome inactivation in X-linked disorders

Research Project

Project/Area Number	17K16293
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Pediatrics
Research Institution	Institute for Developmental Research Aichi Developmental Disability Center
Principal Investigator	Katoh Kimiko 愛知県医療療育総合センター発達障害研究所, 遺伝子医療研究部, 研究員 (30598602)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000) Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	Xq27.3q28欠失 / X連鎖性疾患 / X染色体不活性化 / skewed X inactivation / Skewed X染色体不活性化 / 遺伝子 / 脳・神経
Outline of Final Research Achievements	A heterozygous deletion at Xq27.3q28 including FMR1, AFF2, and IDS causes intellectual disability and developmental delay. Here, I examined two female patients with different clinical features harboring Xq27.3q28 deletion. I assessed X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had almost overlapping deletion at Xq27.3q28, however the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Next, we analyzed a topologically associated domains (TADs) using published Hi-C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. This might lead to misexpression of genes on neo-TADs and affect sever phenotypes of patient 1. Therefore, there is a possibility that the ratio of XCI of the normal X chromosome and TADs alteration influence the clinical differences of patients with deletion at Xq27.3q28.
Academic Significance and Societal Importance of the Research Achievements	本研究により、Xq27.3q28領域に欠失をもつ女性に対しては、その重症度の評価にはX染色体の不活性化状態を調べることが有効であることが示された。欠失をもつX染色体が偏って活性化している場合には、知的障害や運動発達遅滞の程度が重度になる可能性が考えられる。また、欠失領域を正確に同定することで、既存のHiCデータを活用したクロマチン高次構造（topologically associating domains, TADs)の変化予測が可能となる。TADsの変化により欠失領域周辺遺伝子の発現が変化する可能性があるため、TADsの変化を調べることも診断に有効であると考えられる。