Kameda Satoshi, Higo Shuichiro, Shiba Mikio, Kondo Takumi, Li Junjun, Liu Li, Tabata Tomoka, Inoue Hiroyuki, Okuno Shota, Ogawa Shou, Kuramoto Yuki, Yasutake Hideki, Lee Jong-Kook, Takashima Seiji, Ikeda Yoshihiko, Hikoso Shungo, Miyagawa Shigeru, Sakata Yasushi
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Medical Therapeutics for Heart Failure, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
JACC Basic Transl Sci. 2023 Feb 8;8(6):599-613. doi: 10.1016/j.jacbts.2022.11.007. eCollection 2023 Jun.
Study investigators encountered a female Becker muscular dystrophy (BMD) carrier with advanced heart failure (HF) and identified a stop-gain variant in procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 () as a potential second-hit variant. Isogenic induced pluripotent stem cells (iPSCs) with dominant expression of WT-, Δ45-48-, or Δ45-48- with corrected variant were established. Microforce testing using 3-dimensional self-organized tissue rings (SOTRs) generated from iPSC-derived cardiomyocytes (iPSC-CMs) demonstrated that correction of the heterozygous variant did not improve the reduced force, but it significantly recovered the reduced stiffness in Δ45-48- SOTRs. Correction of the variant restored collagen synthesis in iPSC-CMs. Our findings revealed the pathogenesis underlying advanced HF in a female BMD carrier.
研究人员遇到一名患有晚期心力衰竭（HF）的女性贝克肌肉萎缩症（BMD）携带者，并鉴定出脯氨酸赖氨酸2-氧代戊二酸5-双加氧酶3（）中的一个增益性终止变异作为潜在的二次打击变异。建立了野生型-、Δ45-48-或经校正变异的Δ45-48-显性表达的同基因诱导多能干细胞（iPSC）。使用由iPSC衍生的心肌细胞（iPSC-CM）生成的三维自组织组织环（SOTR）进行微力测试表明，杂合变异的校正并未改善降低的力，但它显著恢复了Δ45-48-SOTR中降低的刚度。变异的校正恢复了iPSC-CM中的胶原蛋白合成。我们的研究结果揭示了女性BMD携带者晚期HF的发病机制。
