National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
APHP.Nord, Robert Debré University Hospital, Department of Genetics, Paris, France; Université Paris Cité, Inserm UMR 1141, NeuroDiderot, 75019 Paris, France.
Am J Hum Genet. 2023 Apr 6;110(4):663-680. doi: 10.1016/j.ajhg.2023.03.001. Epub 2023 Mar 24.
The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.
绝大多数人类基因通过可变剪接编码多个异构体，这些异构体的时空调节对生物体的发育和功能至关重要。剪接体（spliceosome）调节和执行剪接反应，主要由小核核糖核蛋白（small nuclear ribonucleoproteins，snRNPs）组成，snRNPs 由小核 RNA（small nuclear RNAs，snRNAs）和蛋白亚基组成。snRNA 基因转录由 snRNA 激活蛋白复合物（snRNA-activating protein complex，SNAPc）起始。在这里，我们报道了 8 个家系中的 10 名个体存在杂合、有害的 SNAPC4 变体。SNAPC4 编码 SNAPc 五个亚基之一，对于 DNA 结合至关重要。大多数受影响的个体表现为运动发育迟缓，出生后第一年出现发育倒退，随后出现进行性痉挛，导致步态改变、截瘫和口运动功能障碍。大多数个体的脑 MRI 显示大脑、小脑或基底节体积减少。在受影响个体的可获得细胞中，与未受影响的对照相比，SNAPC4 的丰度降低，这表明这些杂合变体影响了 SNAPC4 的积累。通过基因组编辑使 HeLa 细胞系中的 SNAPC4 水平降低导致 snRNA 表达降低和可变剪接的全局失调。与未受影响的细胞相比，来自受影响个体的可获得成纤维细胞显示 snRNA 表达降低和可变剪接的全局失调。总之，这些数据表明这些杂合的 SNAPC4 变体导致功能丧失，并导致这些受影响个体的神经退行性变和进行性痉挛。
