講演情報
[OE3-4]CTR9遺伝子による大頭症、知的障害、運動発達遅滞を示す新規疾患報告
○鈴木 寿人1, 青木 佳南2, 黒澤 健司3, 今川 和生4, 大戸 達之4, 山田 茉未子1, 武内 俊樹5, 小崎 健次郎1, 石谷 太2 (1.慶應義塾大学 医学部 臨床遺伝学センター, 2.大阪大学 微生物研究所 環境応答研究部門 生体統御分野, 3.神奈川県立こども医療センター 遺伝科, 4.筑波大学 医学医療系 小児科, 5.慶應義塾大学 医学部 小児科学教室)
CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histone H3K4me3 and H3K36me3. We identified two de novo missense variants (p.(Pro25Arg) and p.(Glu15Asp)) in CTR9 gene in two unrelated patients with common phenotypes; macrocephaly, motor delay, and intellectual disability. To confirm the pathological significance of CTR9 variants, we performed rescue experiments and overexpression studies on ctr9-knockout zebrafish with human wild-type and mutant CTR9 mRNA inserted.
The ctr9-knockout zebrafish showed macrocephaly and poor movement. Those with wild-type mRNA inserted in rescue experiments returned to normal, whereas the co-injection of the two hCTR9 variants did not exhibit such rescue effects. Overexpression studies showed no phenotypic change in the wild type, but the mutant was able to reproduce macrocephaly. The results suggest that the mutants detected have a dominant-negative effect.
We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay, and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.
The ctr9-knockout zebrafish showed macrocephaly and poor movement. Those with wild-type mRNA inserted in rescue experiments returned to normal, whereas the co-injection of the two hCTR9 variants did not exhibit such rescue effects. Overexpression studies showed no phenotypic change in the wild type, but the mutant was able to reproduce macrocephaly. The results suggest that the mutants detected have a dominant-negative effect.
We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay, and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.