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HGNC Approved Gene Symbol: GINS1
SNOMEDCT: 1179286007;
Cytogenetic location: 20p11.21 Genomic coordinates (GRCh38): 20:25,407,673-25,448,563 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.21 | Immunodeficiency 55 | 617827 | Autosomal recessive | 3 |
The yeast heterotetrameric GINS complex is made up of Sld5 (GINS4; 610611), Psf1, Psf2 (GINS2; 610609), and Psf3 (GINS3; 610610). The formation of the GINS complex is essential for the initiation of DNA replication in yeast and Xenopus egg extracts (Ueno et al., 2005).
By sequencing clones obtained from a size-fractionated myeloid leukemia cell line cDNA library, Nagase et al. (1996) cloned GINS1, which they designated KIAA0186. The 3-prime UTR contains a complex array of Alu repeats and partial LINE sequences, and the deduced protein contains 196 amino acids. Northern blot analysis detected moderate expression in thymus, testis, KG-1 cells, and HeLa cells, with low expression in small intestine and colon, and no expression in the other tissues examined.
By RT-PCR of mouse tissues, Ueno et al. (2005) found Psf1 expression predominantly in tissues with active stem cell systems, including adult bone marrow, thymus, testis, and ovary. Expression was not detected in other adult tissues. Immunohistochemical analysis detected Psf1 in immature cells of sperm, i.e., spermatogonia, and in other immature cell populations, including blastocysts, thymic progenitor cells, and yolk sac-containing hematopoietic progenitor cells.
Takayama et al. (2003) found that in yeast during S phase GINS associated first with replication origins and then with neighboring sequences. Without GINS, neither Dpb11, which is a homolog of TOPBP1 (607760), nor Cdc45 (603465) associated properly with chromatin DNA. Without Dpb11 and Sld3, GINS did not associate with replication origins. Genetic and 2-hybrid analysis suggested that GINS interacted with Sld3 and Dpb11. Takayama et al. (2003) concluded that Dpb11, Sld3, Cdc45, and GINS assemble in a mutually dependent manner on replication origins to initiate DNA synthesis.
Maric et al. (2014) showed that the CMG helicase, composed of Cdc45/Mcm (see MCM7, 600592)/GINS, is ubiquitylated during the final stages of chromosome replication in S. cerevisiae, specifically on its Mcm7 subunit. The yeast F-box protein Dia2 is essential in vivo for ubiquitylation of CMG, and the SCF(Dia2) ubiquitin ligase (see 603134) is also required to ubiquitylate CMG in vitro on its Mcm7 subunit in extracts of S-phase yeast cells. Maric et al. (2014) concluded that their data identified 2 key features of helicase disassembly in budding yeast. First, there is an essential role for the F-box protein Dia2, which drives ubiquitylation of the CMG helicase on its Mcm7 subunit. Second, the Cdc48 (601023) segregase is required to break ubiquitylated CMG into its component parts. Once separated from GINS and Cdc45, the Mcm2-7 hexamer is less stable, so that all of the subunits of the CMG helicase are lost from the newly replicated DNA.
By radiation hybrid analysis, Nagase et al. (1996) mapped the GINS1 gene to chromosome 20.
In 5 patients from 4 unrelated families with immunodeficiency-55 (IMD55; 617827), Cottineau et al. (2017) identified compound heterozygous mutations in the GINS1 gene (610608.0001-610608.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Two of the mutations occurred in the 5-prime untranslated region and were demonstrated to cause splicing abnormalities with decreased GINS1 mRNA levels in patient cells. Cells from patients had lower GINS1 protein levels than control cells (40% on average; range, 29-53%), suggesting that both the UTR and missense mutations affected protein levels. Residual full-length wildtype GINS1 mRNA (5-10%) was also detected, consistent with 'leaky' or hypomorphic alleles, and likely explained why the patients survived, since knockdown of the GINS1 gene in mice is embryonic lethal. GINS1 activity ranged from 3 to 16%, depending on the GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. Patient cells showed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which could be rescued by wildtype GINS1. The findings suggested that GINS1 is critical for proper DNA replication and maintenance, particularly in NK cells.
The GINS complex derives its name from the Japanese words Go, Ichi, Nii, and San, which mean 5, 1, 2, and 3, respectively, and refer to the numbering of the yeast homologs of the GINS complex (Takayama et al., 2003).
Ueno et al. (2005) found that Psf1 deletion caused embryonic lethality in mice around the implantation stage. Psf1 -/- blastocysts failed to show outgrowth in culture and exhibited impaired proliferation of the inner cell mass and trophoblast. Ueno et al. (2005) concluded that Psf1 is required for early embryogenesis.
In 2 sisters (patients 1 and 2), born of unrelated French parents (kindred A), and in an 18-year-old unrelated girl (patient 5 from kindred D) with immunodeficiency-55 (IMD55; 617827), Cottineau et al. (2017) identified compound heterozygous mutations in the GINS1 gene: a -48C-G transversion in the 5-prime untranslated region, and a c.247C-T transition in exon 4, resulting in an arg83-to-cys (R83C; 610608.0002) substitution. A 29-year-old woman (patient 4 from kindred C) with the disorder was compound heterozygous for -48C-G and a c.455G-A transition in exon 6, resulting in a cys152-to-tyr (C152Y; 610608.0004) substitution. A 7-year-old boy (patient 3 from kindred B) with the disorder was compound heterozygous for R83C and a -60A-G transition in the 5-prime untranslated region (610608.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Only R83C was found at a low frequency in the 1000 Genomes Project database; R83C and C152Y were found at low frequencies in the ExAC database. The 5-prime mutations were not found in any public databases. Haplotype analysis did not reveal a founder effect for either of the recurrent alleles. Analysis of patient cells showed that the -48C-G and -60A-G mutations resulted in splicing abnormalities with low level production of full-length wildtype GINS1 mRNA (5-10%), consistent with them being 'leaky' or hypomorphic alleles.
For discussion of the c.247C-T transition in exon 4 of the GINS1 gene, resulting in an arg83-to-cys (R83C) substitution, that was found in compound heterozygous state in patients with immunodeficiency-55 (IMD55; 617827) by Cottineau et al. (2017), see 610608.0001.
For discussion of the -60A-G transition in the 5-prime untranslated region of the GINS1 gene that was found in compound heterozygous state in a patient with immunodeficiency-55 (IMD55; 617827) by Cottineau et al. (2017), see 610608.0001.
For discussion of the c.455G-A transition in exon 6 of the GINS1 gene, resulting in a cys152-to-tyr (C152Y) substitution that was found in compound heterozygous state in a patient with immunodeficiency-55 (IMD55; 617827) by Cottineau et al. (2017), see 610608.0001.
Cottineau, J., Kottemann, M. C., Lach, F. P., Kang, Y.-H., Vely, F., Deenick, E. K., Lazarov, T., Gineau, L., Wang, Y., Farina, A., Chansel, M., Lorenzo, L., and 30 others. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J. Clin. Invest. 127: 1991-2006, 2017. [PubMed: 28414293] [Full Text: https://doi.org/10.1172/JCI90727]
Maric, M., Maculins, T., De Piccoli, G., Labib, K. Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science 346: 1253596, 2014. Note: Electronic Article. [PubMed: 25342810] [Full Text: https://doi.org/10.1126/science.1253596]
Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 3: 17-24, 1996. [PubMed: 8724849] [Full Text: https://doi.org/10.1093/dnares/3.1.17]
Takayama, Y., Kamimura, Y., Okawa, M., Muramatsu, S., Sugino, A., Araki, H. GINS, a novel multiprotein complex required for chromosomal DNA replication in budding yeast. Genes Dev. 17: 1153-1165, 2003. [PubMed: 12730134] [Full Text: https://doi.org/10.1101/gad.1065903]
Ueno, M., Itoh, M., Kong, L., Sugihara, K., Asano, M., Takakura, N. PSF1 is essential for early embryogenesis in mice. Molec. Cell Biol. 25: 10528-10532, 2005. [PubMed: 16287864] [Full Text: https://doi.org/10.1128/MCB.25.23.10528-10532.2005]