Alternative titles; symbols
HGNC Approved Gene Symbol: GEMIN2
Cytogenetic location: 14q21.1 Genomic coordinates (GRCh38): 14:39,114,323-39,136,973 (from NCBI)
The SMN gene (see SMN1; 600354) is mutated or deleted in over 98% of patients with spinal muscular atrophy (see SMA; 253300). SMN has been localized to a nuclear compartment called gems (gemini of coiled bodies). Using a yeast 2-hybrid system with SMN as bait, Liu et al. (1997) identified a novel protein, SIP1 (SMN interacting protein-1). SIP1 is expressed as a 1.3-kb transcript that encodes a 279-amino acid protein with a calculated molecular mass of 32 kD. Xenopus SIP1 is 90% identical to human SIP1 at the amino acid level. In addition, human SIP1 has significant identity with S. cerevisiae Brr1, which has been shown to be involved in snRNP biogenesis (see 601664).
Liu et al. (1997) demonstrated that SMN and SIP1 interact tightly in vivo and in vitro and colocalize in gems in the nucleus as well as in the cytoplasm. Immunopurification of the 300-kD SMN-SIP1 complex showed that it contains, besides SMN and SIP1, spliceosomal snRNP core proteins. SMN interacted with several snRNP Sm core proteins and contains 2 distinct binding sites, one for SIP1 and one for the Sm proteins.
Studies in Xenopus oocytes by Fischer et al. (1997) demonstrated that the SMN-SIP1 complex is associated with spliceosomal snRNAs U1 (180680) and U5 (180691) in the cytoplasm. Antibodies directed against the SMN-SIP1 complex strongly interfered with the cytoplasmic assembly of the common (Sm) snRNP proteins with spliceosomal snRNAs and with the import of the snRNP complex into the nucleus. Fischer et al. (1997) concluded that the SMN-SIP1 complex is directly involved in the biogenesis of spliceosomal snRNPs. The authors suggested that defects in spliceosomal snRNP biogenesis are the cause of SMA.
Hannus et al. (2000) determined that the Schizosaccharomyces pombe protein Yab8p is structurally and functionally related to SMN found in higher eukaryotes. Yab8p interacts with a novel yeast protein termed Yip1p, which exhibits homology to SIP1. Yab8p interacts via its N terminus with Yip1p in a manner similar to SMN-SIP1 binding. In a conditional knockout yeast strain, suppression of Yab8 expression caused nuclear accumulation of poly(A) mRNA and inhibition of splicing. The authors concluded thatYab8p is a novel factor involved in splicing, and suggested that Yab8p exerts a function similar or identical to the nuclear pool of SMN, while Yip1p is the likely homolog of SIP1.
Meister et al. (2000) showed that a monoclonal antibody directed against SMN inhibits pre-mRNA splicing. Using biochemical fractionation and anti-SMN immunoaffinity chromatography, they identified 2 distinct nuclear SMN complexes, termed NSC1 and NSC2. NSC1 is a U snRNA-free 20S complex containing at least 10 proteins, including SIP1, the putative helicase dp103/Gemin3, and the novel dp103/Gemin3-interacting protein GIP1/Gemin4. NSC1 also contains a specific subset of spliceosomal Sm proteins, suggesting that the SMN-Sm protein interaction is not restricted to the cytoplasm. The authors concluded that nuclear SMN affects splicing by modulating the Sm protein composition of U snRNPs.
Young et al. (2000) used biomolecular interaction analysis to demonstrate that SMN self-association occurs via regions encoded by exons 2b and 6, that exon 2b encodes a binding site for SIP1, and that an interaction also occurs between exon 2- and 4-encoded regions within the SMN monomer. Dimerization of SMN was not required for SIP1 binding. The authors presented a model wherein linear oligomers or closed rings might be formed from SMN monomers, which is thought to be a prerequisite for SMN to engage in RNA splicing.
Jablonka et al. (2001) showed by confocal immunofluorescence studies that a significant amount of Smn does not colocalize with Sip1 in neurites of motor neurons, suggesting that Smn may exert motor neuron-specific functions that are not dependent on Sip1. Sip1 was highly expressed in spinal cord during early murine development, and expression decreased in parallel with Smn during postnatal development. Reduced production of Smn in cell lines derived from SMA patients or in a transgenic mouse model for SMA coincided with a simultaneous reduction of Sip1, suggesting to the authors that expression of Sip1 and Smn may be tightly coregulated.
Carissimi et al. (2006) found that GEMIN6 (607006), GEMIN7 (607419), and UNRIP (STRAP; 605986) associated in a stable cytoplasmic complex in the absence of the SMN complex. GEMIN8 (300962) bound directly to SMN and mediated interaction of GEMIN6-GEMIN7-UNRIP with SMN and GEMIN2. Knockdown of GEMIN8 abrogated interaction of GEMIN6-GEMIN7-UNRIP with the SMN complex, reduced the association of Sm proteins with the SMN complex, and impaired Sm core formation. Carissimi et al. (2006) concluded that GEMIN6, GEMIN7, GEMIN8, and UNRIP are required for efficient association of Sm proteins with the SMN complex.
Helmken et al. (2000) determined that the SIP1 gene contains 10 exons. They also identified 5 transcription isoforms.
Since both SMN1 and SIP1 belong to the same pathway and are part of the same protein complex, Helmken et al. (2000) questioned whether mutations within SIP1 are responsible for both the phenotypic variability and the appearance of non-SMN mutated SMA patients (about 4% of most SMA patient groups). By fluorescence in situ hybridization, they mapped the SIP1 gene to 14q13-q21. They noted that no SMA-related disorder had been assigned to that chromosome region.
Hartz (2015) mapped the GEMIN2 gene to chromosome 14q21.1 based on an alignment of the GEMIN2 sequence (GenBank AB037701) with the genomic sequence (GRCh38).
Exclusion Studies
Helmken et al. (2000) sequenced the entire coding region from 23 typical SMA patients who had failed to show any SMN1 mutation. No mutation or polymorphism was found within SIP1. Additionally, they sequenced the entire SIP1 coding region from 26 SMA sibs of 11 SMA families with identical genotypes at the SMN1 locus but different phenotypes, and again no mutation was found. Finally, no difference in expression level of the 5 isoforms among phenotypically variable sibs was observed. Based on these data, Helmken et al. (2000) suggested that neither the phenotypic variability nor the 5q-unlinked SMA is caused by mutations within SIP1.
Carissimi, C., Saieva, L., Gabanella, F., Pellizzoni, L. Gemin8 is required for the architecture and function of the survival motor neuron complex. J. Biol. Chem. 281: 37009-37016, 2006. [PubMed: 17023415] [Full Text: https://doi.org/10.1074/jbc.M607505200]
Fischer, U., Liu, Q., Dreyfuss, G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 90: 1023-1029, 1997. [PubMed: 9323130] [Full Text: https://doi.org/10.1016/s0092-8674(00)80368-2]
Hannus, S., Buhler, D., Romano, M., Seraphin, B., Fischer, U. The Schizosaccharomyces pombe protein Yab8p and a novel factor, Yip1p, share structural and functional similarity with the spinal muscular atrophy-associated proteins SMN and SIP1. Hum. Molec. Genet. 9: 663-674, 2000. [PubMed: 10749973] [Full Text: https://doi.org/10.1093/hmg/9.5.663]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/29/2015.
Helmken, C., Wetter, A., Rudnik-Schoneborn, S., Liehr, T., Zerres, K., Wirth, B. An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA). Europ. J. Hum. Genet. 8: 493-499, 2000. [PubMed: 10909848] [Full Text: https://doi.org/10.1038/sj.ejhg.5200479]
Jablonka, S., Bandilla, M., Wiese, S., Buhler, D., Wirth, B., Sendtner, M., Fischer, U. Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. Hum. Molec. Genet. 10: 497-505, 2001. [PubMed: 11181573] [Full Text: https://doi.org/10.1093/hmg/10.5.497]
Liu, Q., Fischer, U., Wang, F., Dreyfuss, G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90: 1013-1021, 1997. [PubMed: 9323129] [Full Text: https://doi.org/10.1016/s0092-8674(00)80367-0]
Meister, G., Buhler, D., Laggerbauer, B., Zobawa, M., Lottspeich, F., Fischer, U. Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. Hum. Molec. Genet. 9: 1977-1986, 2000. [PubMed: 10942426] [Full Text: https://doi.org/10.1093/hmg/9.13.1977]
Young, P. J., Man, N., Lorson, C. L., Le, T. T., Androphy, E. J., Burghes, A. H. M., Morris, G. E. The exon 2b region of the spinal muscular atrophy protein, SMN, is involved in self-association and SIP1 binding. Hum. Molec. Genet. 9: 2869-2877, 2000. Note: Erratum: Hum. Molec. Genet. 10: 88 only, 2001. [PubMed: 11092763] [Full Text: https://doi.org/10.1093/hmg/9.19.2869]