Alternative titles; symbols
HGNC Approved Gene Symbol: SNRPE
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:203,861,599-203,871,152 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | Hypotrichosis 11 | 615059 | Autosomal dominant | 3 |
SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome (summary by Pasternack et al., 2013).
Many patients with systemic lupus erythematosus (152700) circulate Sm autoantibodies directed against a broad range of small nuclear ribonucleoprotein complexes (snRNPs). One of the proteins recognized by some anti-Sm sera is the 11,000-Da E protein. This protein is 1 of 4 'core' proteins associated with all known snRNAs in the U family (U1, U2, U4, U5, and U6) (Wieben et al., 1985; Stanford et al., 1987).
Stanford et al. (1988) gave the complete nucleotide sequence. The longest open reading frame coded for a basic 92-amino acid protein that had an amino acid sequence in perfect agreement with that obtained from purified E protein.
After RT-PCR, Pasternack et al. (2013) performed semiquantitative PCR and found that SNRPE is expressed ubiquitously, including in skin and hair follicle cells. Immunohistochemistry revealed SNRPE in the nuclei of all cells of the hair follicle, the epidermis, and the dermis. An identical pattern of SNRPE immunoreactivity was observed in dorsal skin of 9-day-old C57BL/6J mice.
The gene for the E protein is 9 kb long and contains 5 exons. The sequence is known for 9 closely related genes that have several features of processed pseudogenes (Neiswanger et al., 1988).
Neiswanger et al. (1988, 1990) mapped the E protein gene to 1q32 by a combination of somatic cell and in situ hybridization. Neiswanger et al. (1990) corroborated the assignment by genetic linkage to markers in the region of 1q32. They noted that at least one of the SNRPE pseudogenes is linked to a signal transduction G protein gene (139380) that also maps to chromosome 1. Two other small nuclear ribonucleoprotein (snRNP) components--the U1 RNA 'true' multigene family (180680) and a group of class I U1 pseudogenes--are located on chromosome 1. A U2 snRNA gene cluster (RNU2; 180690) is located on chromosome 17, whereas chromosome 19 encodes the U1-specific 70K protein (180740).
Hypotrichosis 11
In affected members of a 4-generation Spanish family and 2 sporadic patients with hypotrichosis (HYPT11; 615059), Pasternack et al. (2013) identified heterozygosity for 2 different mutations in the SNRPE gene (128260.0001 and 128260.0002). Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRPSs was normal, suggesting the variants alter the function of U snRNPs in splicing rather than their biogenesis.
In 3 unrelated patients with hypotrichosis, Pan et al. (2021) identified heterozygosity for mutations in the SNRPE gene: a 21-year-old Turkish woman carried the previously reported start codon variant c.1A-G (128260.0001), a 6-year-old Chinese girl had a de novo splice site variant (128260.0003), and a 2.5-year-old Spanish boy carried a de novo missense mutation (L74P; 128260.0004). The authors noted that none of the patients exhibited microcephaly or impaired intellectual development.
Associations Pending Confirmation
In a 15-year-old German girl with microcephaly, intellectual disability, developmental delay, accessory spleen, incomplete right bundle branch block, and IgA deficiency, who was negative for mutation in known microcephaly- and seizure-associated genes, Chen et al. (2019) identified heterozygosity for a de novo c.65T-C transition in the SNRPE gene, resulting in a phe22-to-ser (F22S) substitution at a highly conserved residue within a binding module. Functional analysis in patient fibroblasts indicated that the F22S mutant fails to enter the biogenesis pathway of spliceosomal U snRNP, resulting in aberrant mRNA splicing and alteration of the gene expression program. Brain MRI showed heterotopias. Clinical information was limited, and scalp/body hair was not described.
In a 4-year-old boy with microcephaly, intellectual disability, atrichia, and multiple congenital anomalies, including large anteverted simple ears, retrognathia, cleft palate, duplicated right thumb, and ectopic (pelvic) left kidney, Amudhavalli et al. (2023) identified heterozygosity for a de novo deletion (c.82-28_82-16del) in intron 2 of the SNRPE gene that was not found in public variant databases. Sequencing of cDNA demonstrated that the mutation causes in-frame skipping of exon 3, removing 21 amino acids (Arg28_Ile48del) that constitute more than 20% of the protein. Brain MRI showed mild simplification of the frontal lobe gyral pattern and mild ventriculomegaly, as well as bilateral hypoplastic semicircular canals and dysplastic vestibules.
Using a targeted morpholino, Chen et al. (2019) generated snrpe-deficient zebrafish and observed a significant decrease in head size (25%) in the morphants compared to controls. Coinjection of the morpholino with wildtype snrpe lacking the binding site for the morpholino rescued the phenotype. Analysis of expression profiles in morphants showed thousands of differentially expressed genes (DEGs) compared to control fish; the number of DEGs was drastically reduced upon coexpression of wildtype snrpe, whereas fish coexpressing mutant snrpe bearing a point mutation showed DEG numbers comparable to the morphants. In addition, the increase in aberrant splicing induced by snrpe deficiency in the morphants could be rescued by expressing wildtype but not mutant snrpe. The authors suggested that the small brain size associated with snrpe deficiency is likely a consequence of altered gene expression and aberrant splicing.
In affected members of a 4-generation Spanish family with hypotrichosis (HYPT11; 615059), previously reported by Just et al. (1998), and an unrelated 12-year-old British girl, Pasternack et al. (2013) identified heterozygosity for a 1A-G transition in the SNRPE gene, altering the start codon (MET1) of the gene. The mutation segregated with disease in both families and was not found in 880 German or 598 Spanish control chromosomes, or in the dbSNP or 1000 Genomes Project databases. Western blot analyses of HEK293T cells expressing SNRPE 1A-G revealed an N-terminally truncated protein, suggesting that the mutation might result in use of an alternative in-frame downstream start codon.
In a 21-year-old Turkish woman (case 3) with sparse hair and absent eyebrows, Pan et al. (2021) identified heterozygosity for the c.1A-G mutation in the SNRPE gene.
In an 8-year-old Tunisian boy with hypotrichosis (HYPT11; 615059), Pasternack et al. (2013) identified heterozygosity for a 133G-A transition in the SNRPE gene, resulting in a gly45-to-ser (G45S) substitution at a highly conserved residue in the Sm motif 1. His parents were reported to be unaffected but were not available for analysis. The mutation was not found in 880 German control chromosomes or 598 Spanish control chromosomes, and was not present in the dbSNP or the 1000 Genomes Project databases. Functional analysis in HEK293T cells showed reduced incorporation of the mutant into U snRNP compared to wildtype.
In a 6-year-old Chinese girl (case 1) with hypotrichosis (HYPT11; 615059), Pan et al. (2021) identified heterozygosity for a de novo splice site mutation (c.54+2T-A) in intron 1 of the SNRPE gene that was not found in 200 Chinese control chromosomes or in the dbSNP or 1000 Genomes Project databases. In vitro minigene analysis revealed that the mutation causes complete skipping of exon 1 and partial (14-bp) retention of intron 1.
In a 2.5-year-old Spanish boy (case 2) with congenital hypotrichosis (HYPT11; 615059), Pan et al. (2021) identified heterozygosity for a c.221T-C transition in exon 4 of the SNRPE gene, resulting in an leu74-to-pro (L74P) substitution at a highly conserved residue. The mutation was not found in his unaffected parents or in the dbSNP or 1000 Genomes Project databases.
Amudhavalli, S. M., Paolillo, V., Lawson, C., Patterson, M., Kussmann, J., Nopper, A. J., Lypka, M., Saunders, C. Novel blended SNRPE-related spliceosomopathy phenotype characterized by microcephaly and congenital atrichia. Am. J. Med. Genet. 191A: 1425-1429, 2023. [PubMed: 36814386] [Full Text: https://doi.org/10.1002/ajmg.a.63149]
Chen, T., Zhang, B., Ziegenhals, T., Prusty, A. B., Frohler, S., Grimm, C., Hu, Y., Schaefke, B., Fang, L., Zhang, M., Kraemer, N., Kaindl, A. M., Fischer, U., Chen, W. A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing. PLoS Genet. 15: e1008460, 2019. [PubMed: 31671093] [Full Text: https://doi.org/10.1371/journal.pgen.1008460]
Just, M., Ribera, M., Fuente, M. J., Bielsa, I., Ferrandiz, C. Hereditary hypotrichosis simplex. Dermatology 196: 339-342, 1998. [PubMed: 9621144] [Full Text: https://doi.org/10.1159/000017909]
Neiswanger, K., Stanford, D. R., Sparkes, R. S., Nishimura, D., Mohandas, T., Klisak, I., Heinzmann, C., Wieben, E. D. Assignment of the gene for the small nuclear ribonucleoprotein E (SNRPE) to human chromosome 1q25-q43. Genomics 7: 503-508, 1990. [PubMed: 2143747] [Full Text: https://doi.org/10.1016/0888-7543(90)90192-w]
Neiswanger, K., Stanford, D. R., Wieben, E. D., Mohandas, T., Klisak, I., Heinzmann, C., Sparkes, R. S. Regional assignment of the gene for the snRNP protein 'E' by in situ hybridization to human chromosome 1q2.5-q4.3. (Abstract) Am. J. Hum. Genet. 43: A153 only, 1988.
Pan, C., Humbatova, A., Zheng, L., Cesarato, N., Grimm, C., Chen, F., Blaumeiser, B., Catalan-Lamban, A., Patino-Garcia, A., Fischer, U., Cheng, R., Li, Y., Yu, X., Yao, Z., Li, M., Betz, R. C. Additional causal SNRPE mutations in hereditary hypotrichosis simplex. Brit. J. Derm. 185: 439-441, 2021. [PubMed: 33792916] [Full Text: https://doi.org/10.1111/bjd.20089]
Pasternack, S. M., Refke, M., Paknia, E., Hennies, H. C., Franz, T., Schafer, N., Fryer, A., van Steensel, M., Sweeney, E., Just, M., Grimm, C., Kruse, R., Ferrandiz, C., Nothen, M. M., Fischer, U., Betz, R. C. Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex. Am. J. Hum. Genet. 92: 81-87, 2013. [PubMed: 23246290] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.022]
Stanford, D. R., Kehl, M., Perry, C. A., Holicky, E. L., Harvey, S. E., Rohleder, A. M., Rehder, K., Jr., Luhrmann, R., Wieben, E. D. The complete primary structure of the human snRNP E protein. Nucleic Acids Res. 16: 10593-10605, 1988. [PubMed: 2974536] [Full Text: https://doi.org/10.1093/nar/16.22.10593]
Stanford, D. R., Rohleder, A., Neiswanger, K., Wieben, E. D. DNA sequence of a human Sm autoimmune antigen: the multigene family contains a processed pseudogene. J. Biol. Chem. 262: 9931-9934, 1987. [PubMed: 2440864]
Wieben, E. D., Rohleder, A. M., Nenninger, J. M., Pederson, T. cDNA cloning of a human autoimmune nuclear ribonucleoprotein antigen. Proc. Nat. Acad. Sci. 82: 7914-7918, 1985. [PubMed: 2999783] [Full Text: https://doi.org/10.1073/pnas.82.23.7914]