Alternative titles; symbols
HGNC Approved Gene Symbol: SNAPC4
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:136,375,571-136,400,170 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction | 620515 | Autosomal recessive | 3 |
SNAPC4 encodes a subunit of the snRNA-activating protein complex (SNAPc), which is required for transcription of both RNA polymerase II and III snRNA genes (see SNAPC1, 600591) (Wong et al., 1998).
Wong et al. (1998) reported that SNAPc consists of at least 4 subunits, 3 of which, SNAPC1, SNAPC2 (605076), and SNAPC3 (602348), had been cloned. Using sequences derived from purified SNAPc, Wong et al. (1998) assembled a cDNA open reading frame for SNAPC4 (SNAP190), the largest known subunit of the SNAP complex (190 kD), by a combination of library screens and direct RT-PCR. The 1,469-amino acid protein encoded by this sequence contains a Myb protein domain followed by arginine- and serine-rich regions, and a carboxy-terminal region with a leucine zipper-like motif.
Wong et al. (1998) showed that SNAPC4 is required for both RNA polymerase II and III transcription of snRNA genes and that it interacts strongly with SNAPC2 but not with SNAPC1 or SNAPC3. In addition, they found that whereas full-length SNAPC4 protein did not bind to the PSE, a truncated protein containing the Rc and Rd repeats within the Myb domain was able to bind DNA specifically. The carboxy-terminal half of SNAPC4 can interact with DNA-bound transcription activator OCT1 (164175).
Gross (2014) mapped the SNAPC4 gene to chromosome 9q34.3 based on an alignment of the SNAPC4 sequence (GenBank BC172433) with the genomic sequence (GRCh37).
In 10 patients from 8 unrelated families with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515), Frost et al. (2023) identified homozygous or compound heterozygous putative loss-of-function mutations in the SNAPC4 gene (see, e.g., 602777.0001-602777.0007). The patients were ascertained through the GeneMatcher program after genetic analysis identified biallelic mutations through trio-based whole-exome or whole-genome sequencing. The mutations, which were confirmed by Sanger sequencing, segregated with the disorder in all families and were absent from or present at a low frequency in the gnomAD database. SNAPC4-deficient HeLa cells showed a nonsignificant reduction in overall snRNA expression by about 50% compared to controls. However, expression of RNU4-1, RNU4ATAC (601428), and RNU5A-1 (180691) were significantly reduced compared to controls. RNA-seq analysis detected 7,496 differentially spliced alternative splicing events in SNAPC4-deficient cells compared to controls, and Gene Ontology analysis indicated that affected genes were involved in RNA splicing, transport, and processing, as well as microtubule regulation during mitosis. Similar to SNAPC4-deficient HeLa cells, patient fibroblasts and lymphoblastoid cells showed an overall decrease in SNAPC4 mRNA and protein expression, and fibroblasts showed decreased expression of certain snRNAs (particularly RNU2-1 (180690) and RNU5A-1); other RNU species were variably decreased compared to controls. RNA-seq analysis of patient fibroblasts detected 5,523 differentially spliced alternative splicing events compared to controls, also with involvement of genes involved in RNA dynamics and microtubule cytoskeleton organization involved in mitosis. The findings in both cell models suggested that SNAPC4 mutations impair snRNA transcription and have broad consequences on alternative splicing throughout the transcriptome.
In a 13-year-old girl (P2) with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515), Frost et al. (2023) identified compound heterozygous mutations in the SNAPC4 gene: a c.595G-A transition (c.595G-A, NM_003086.3) in exon 7, resulting in an asp199-to-asn (D199N) substitution, and an intronic G-to-T transversion (c.1325+1G-T; 602777.0002), resulting in a splicing defect, frameshift, and premature termination (Arg434GlyfsTer10) in the DNA-binding domain. The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The D199N mutation was found at a low frequency in gnomAD (0.0032%), whereas the splicing mutation was absent from gnomAD. Patient fibroblasts showed an overall decrease in SNAPC4 mRNA and protein expression, global dysregulation of alternative splicing, and impaired transcription of snRNAs.
For discussion of the c.1325+1G-T transversion (c.1325+1G-T, NM_003086.3) in intron 13 of the SNAPC4 gene, resulting in a splicing defect, frameshift, and premature termination (Arg434GlyfsTer10) in the DNA-binding domain, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515) by Frost et al. (2023), see 602777.0001.
In 2 sibs (P3 and P4), born of unrelated Caucasian parents (family 3), with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515), Frost et al. (2023) identified compound heterozygous mutations in the SNAPC4 gene: a c.1321G-A transition (c.1321G-A, NM_003086.3), resulting in an asp441-to-asn (D441N) substitution in the DNA-binding domain, and a c.1157A-G transition in exon 12, resulting in a gln386-to-arg (Q386R; 602777.0004) substitution also in the DNA-binding domain. The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. D441N was not present in gnomAD, whereas Q386R was found at a low frequency (0.0012%). Patient fibroblasts showed an overall decrease in SNAPC4 mRNA and protein expression, global dysregulation of alternative splicing, and impaired transcription of snRNAs.
For discussion of the c.1157A-G transition (c.1157A-G, NM_003086.3) in exon 12 of the SNAPC4 gene, resulting in a gln386-to-arg (Q386R; 602777.0004) substitution in the DNA-binding domain, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NDRSO; 620515) by Frost et al. (2023), see 602777.0003.
In a 9-year-old Caucasian girl of Dutch descent (P6) with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515), Frost et al. (2023) identified compound heterozygous mutations in the SNAPC4 gene: a c.2428C-T transition (c.2428C-T, NM_003086.3) in exon 20, resulting in an arg810-to-ter (R810X) substitution, and a G-to-T transversion in intron 8 (c.737+5G-T; 602777.0006), resulting in a splicing defect, frameshift, and premature termination (Asn245LysfsTer1). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. R810X was found at a low frequency in gnomAD (0.0011%), whereas the splice site mutation was absent from gnomAD. Patient fibroblasts showed an overall decrease in SNAPC4 mRNA and protein expression, global dysregulation of alternative splicing, and impaired transcription of snRNAs.
For discussion of the G-to-T transversion in intron 8 of the SNAPC4 gene (c.737+5G-T, NM_003086.3), resulting in a splicing defect, frameshift, and premature termination (Asn245LysfsTer1) that was found in compound heterozygous state in a patient with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515) by Frost et al. (2023), see 602777.0005.
In 3 patients (P7, P8, and P9) from 2 unrelated consanguineous Moroccan families (families 6 and 7) with neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction (NEDRSO; 620515), Frost et al. (2023) identified a homozygous G-to-A transition in intron 21 of the SNAPC4 gene (c.2527+1G-A, NM_003086.3), resulting in a splicing defect, frameshift and premature termination (Ser835ThrfsTer86). The mutation, which was found by trio-based whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The mutation was found at a low frequency in the gnomAD database (0.0004%). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
Frost, F. G., Morimoto, M., Sharma, P., Ruaud, L., Belnap, N., Calame, D. G., Uchiyama, Y., Matsumoto, N., Oud, M. M., Ferreira, E. A., Narayanan, V., Rangasamy, S., and 27 others. Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis. Am. J. Hum. Genet. 110: 663-680, 2023. [PubMed: 36965478] [Full Text: https://doi.org/10.1016/j.ajhg.2023.03.001]
Gross, M. B. Personal Communication. Baltimore, Md. 4/16/2014.
Wong, M. W., Henry, R. W., Ma, B., Kobayashi, R., Klages, N., Matthias, P., Strubin, M., Hernandez, N. The large subunit of basal transcription factor SNAPc is a Myb domain protein that interacts with Oct-1. Molec. Cell. Biol. 18: 368-377, 1998. [PubMed: 9418884] [Full Text: https://doi.org/10.1128/MCB.18.1.368]