Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.

TitleBi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.
Publication TypeJournal Article
Year of Publication2023
AuthorsF Frost, G, Morimoto, M, Sharma, P, Ruaud, L, Belnap, N, Calame, DG, Uchiyama, Y, Matsumoto, N, Oud, MM, Ferreira, EA, Narayanan, V, Rangasamy, S, Huentelman, M, Emrick, LT, Sato-Shirai, I, Kumada, S, Wolf, NI, Steinbach, PJ, Huang, Y, Pusey, BN, Passemard, S, Levy, J, Drunat, S, Vincent, M, Guet, A, Agolini, E, Novelli, A, Digilio, MCristina, Rosenfeld, JA, Murphy, JL, Lupski, JR, Vezina, G, Macnamara, EF, Adams, DR, Acosta, MT, Tifft, CJ, Gahl, WA, Malicdan, MChristine
Corporate AuthorsUndiagnosed Diseases Network
JournalAm J Hum Genet
Date Published2023 Apr 06
KeywordsAdolescent, Alleles, Alternative Splicing, Child, Child, Preschool, DNA-Binding Proteins, Female, HeLa Cells, Humans, Infant, Male, Paraparesis, Spastic, Pedigree, Protein Isoforms, Protein Structure, Secondary, RNA, Small Nuclear, RNA-Seq, Transcription Factors

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.

Alternate JournalAm J Hum Genet
PubMed ID36965478
PubMed Central IDPMC10119142
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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