Knierim Ellen, Hirata Hiromi, Wolf Nicole I, Morales-Gonzalez Susanne, Schottmann Gudrun, Tanaka Yu, Rudnik-Schöneborn Sabine, Orgeur Mickael, Zerres Klaus, Vogt Stefanie, van Riesen Anne, Gill Esther, Seifert Franziska, Zwirner Angelika, Kirschner Janbernd, Goebel Hans Hilmar, Hübner Christoph, Stricker Sigmar, Meierhofer David, Stenzel Werner, Schuelke Markus
Department of Neuropediatrics, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258, Japan; Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan.
Am J Hum Genet. 2016 Mar 3;98(3):473-489. doi: 10.1016/j.ajhg.2016.01.006. Epub 2016 Feb 25.
Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.
转录信号共整合因子与转录因子或核受体相关联，并共同调节组织特异性基因转录。我们报告了两个基因（TRIP4和ASCC1）中的隐性功能丧失突变，这两个基因编码核激活信号共整合因子1（ASC-1）复合物的亚基。我们使用纯合性定位和全外显子组测序在四个家族中寻找致病突变。受影响的个体表现出产前发病的脊髓性肌萎缩（SMA）、多发性先天性挛缩（先天性多发性关节挛缩症）、呼吸窘迫和先天性骨折。我们鉴定出纯合和复合杂合的无义突变和移码TRIP4和ASCC1突变，这些突变导致相应蛋白质的截短或完全缺失，并与疾病表型共分离。Trip4和Ascc1在17.5天大的小鼠胚胎中具有相同的表达模式，在脊髓、脑、椎旁神经节、甲状腺和下颌下腺中表达水平较高。在斑马鱼中，反义吗啉代介导的trip4或ascc1敲低破坏了α运动神经元生长以及肌节和神经肌肉接头形成的高度模式化和协调过程，并导致幼虫出现游泳缺陷。ASC-1复合物的免疫沉淀始终共纯化了富含半胱氨酸和甘氨酸的蛋白质1（CSRP1），这是一种转录辅因子，已知其参与成年斑马鱼受伤后的脊髓再生。ASCC1突变的成纤维细胞下调了与神经发生、神经元迁移和路径寻找相关的基因（SERPINF1、DAB1、SEMA3D、SEMA3A），以及与骨骼发育相关的基因（TNFRSF11B、RASSF2、STC1）。我们的研究结果表明，转录共激活复合物的功能障碍可导致影响神经肌肉系统的临床综合征。
