Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.
СтатьяResearch Support, N.I.H., IntramuralПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Frost F Graeme, Morimoto Marie, Sharma Prashant, Ruaud Lyse, Belnap Newell, Calame Daniel G, Uchiyama Yuri, Matsumoto Naomichi, Oud Machteld M, Ferreira Elise A, Narayanan Vinodh, Rangasamy Sampath, Huentelman Matt, Emrick Lisa T, Sato-Shirai Ikuko, Kumada Satoko, Wolf Nicole I, Steinbach Peter J, Huang Yan, Undiagnosed Diseases Network, Pusey Barbara N, Passemard Sandrine, Levy Jonathan, Drunat Séverine, Vincent Marie, Guet Agnès, Agolini Emanuele, Novelli Antonio, Digilio Maria Cristina, Rosenfeld Jill A, Murphy Jennifer L, Lupski James R, Vezina Gilbert, Macnamara Ellen F, Adams David R, Acosta Maria T, Tifft Cynthia J, Gahl William A, Malicdan May Christine V
Аннотация
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.