Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hum Mutat. 2022 Sep;43(9):1224-1233. doi: 10.1002/humu.24397. Epub 2022 May 11.
Nemaline myopathies (NEMs) are genetically and clinically heterogenous. Biallelic or monoallelic variants in TNNT1, encoding slow skeletal troponin T1 (TnT1), cause NEM. We report a 2-year-old patient and his mother carrying the heterozygous TNNT1 variant c.194A>C/p.(Asp65Ala) that occurred de novo in the mother. Both had muscle hypotrophy and muscle weakness. Muscle pathology in the proband's mother revealed slow twitch type 1 fiber hypotrophy and fast twitch type 2 fiber hypertrophy that was confirmed by a reduced ratio of slow skeletal myosin to fast skeletal myosin type 2a. Reverse transcription polymerase chain reaction and immunoblotting data demonstrated increased levels of high-molecular-weight TnT1 isoforms in skeletal muscle of the proband's mother that were also observed in some controls. In an overexpression system, complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced. The previously reported TnT1-E104V and TnT1-L96P mutants showed reduced or no co-immunoprecipitation with TPM3. Our studies support pathogenicity of the TNNT1 p.(Asp65Ala) variant.
杆状体肌病（Nemaline myopathies，NEMs）具有遗传和临床异质性。编码慢肌肌钙蛋白 T1（TnT1）的 TNNT1 基因的双等位基因或单等位基因突变可导致 NEM。我们报告了一名 2 岁的患者及其携带 TNNT1 基因 c.194A>C/p.(Asp65Ala)杂合变异的母亲，该变异是其母亲新发的。两人均存在肌肉萎缩和肌无力。先证者母亲的肌肉病理学显示慢肌 1 型纤维萎缩和快肌 2 型纤维肥大，这通过慢肌肌球蛋白与快肌肌球蛋白 2a 的比例降低得到证实。逆转录聚合酶链反应和免疫印迹数据显示，先证者母亲的骨骼肌中存在高水平的高分子量 TnT1 同工型，一些对照中也观察到了这种情况。在过表达系统中，TnT1-D65A 与原肌球蛋白 3（TPM3）的复合物形成增强。先前报道的 TnT1-E104V 和 TnT1-L96P 突变体与 TPM3 的共免疫沉淀减少或不存在。我们的研究支持 TNNT1 p.(Asp65Ala)变异的致病性。
