HGNC Approved Gene Symbol: RINT1
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38) : 7:105,532,201-105,567,677 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.3 | Infantile liver failure syndrome 3 | 618641 | Autosomal recessive | 3 |
The RINT1 gene encodes a protein that interacts with ZW10 (603954) and NBAS (608025) in the NRZ complex, which is involved in docking and fusion of transport vesicles during vesicular trafficking between the ER and Golgi apparatus (summary by Cousin et al., 2019).
Using a C-terminal fragment of RAD50 (604040) as bait in a yeast 2-hybrid screen of a human B-cell cDNA library, Xiao et al. (2001) cloned RINT1. The deduced 792-amino acid protein has several leucine heptad repeats that form an N-terminal coiled-coil region. Western blot analysis of human cell lines detected an 87-kD RINT1 doublet. Further experiments suggested that the higher molecular mass protein may be translated from an upstream non-AUG start codon.
By immunohistochemical analysis, Lin et al. (2007) found that RINT1 was expressed in endoplasmic reticulum (ER), Golgi apparatus, and centrosomes of human HeLa and U2OS cells.
By genomic sequence analysis, Xiao et al. (2001) mapped the RINT1 gene to chromosome 7q22.1.
Using truncated proteins, Xiao et al. (2001) found that the second leucine heptad repeat of RAD50 and amino acids 257 to 792 of RINT1 were required for RAD50-RINT1 interaction. RINT1 bound RAD50 only during late S and G2/M phases, and human breast cancer cells expressing an N-terminally truncated RINT1 protein displayed defective radiation-induced G2/M checkpoint. Xiao et al. (2001) concluded that RINT1 may play a role in cell cycle control after DNA damage.
Kong et al. (2006) found that RBL2 (180203) and RINT1 were essential for telomere length control in human fibroblasts, with loss of either protein leading to longer telomeres. They proposed that RBL2 forms a complex with RAD50 through RINT1 to block telomerase-independent telomere lengthening.
Using RNA interference, Lin et al. (2007) found that depletion of RINT1 in HeLa cells led to loss of pericentriolar positioning and dispersal of the Golgi apparatus, concurrent with centrosome amplification in interphase. In synchronized cells, RINT1 deficiency led to multiple abnormalities upon mitotic entry, including aberrant Golgi dynamics during early mitosis and defective reassembly at telophase, formation of multiple spindle poles, and missegregation of chromosomes. Mitotic cells underwent cell death due to overwhelming cellular defects. Lin et al. (2007) concluded that RINT1 is essential to maintain the dynamic integrity of the Golgi apparatus and the centrosome.
Docking and fusion of transport vesicles with target membranes requires membrane tethering factors and membrane fusion factors, or SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors). Arasaki et al. (2013) stated that RINT1 functions as a component of an ER tethering complex that interacts with SNAREs at the ER. This tethering complex also includes ZW10 (603954) and NAG (NBAS; 608025). Using immunoprecipitation and binding studies, Arasaki et al. (2013) found that RINT1 also interacted with the octameric COG complex (see COG1, 606973) at the trans-Golgi network (TGN), and that the COG complex bound SNAREs at the TGN. At the TGN, RINT1 interacted directly with the COG component COG1 and with the SNARE component syntaxin-16 (STX16; 603666). The same N-terminal domain of RINT1 was required for interaction with ZW10 at the ER and with COG1 at the TGN, suggesting a switching mechanism. Knockdown of RINT1 in human cell lines inhibited endosome-to-trans-Golgi vesicle trafficking and caused redistribution of TGN marker proteins to endosomes.
In 3 unrelated children with infantile liver failure syndrome-3 (ILFS3; 618641), Cousin et al. (2019) identified compound heterozygous mutations in the RINT1 gene (610089.0001-610089.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All 3 patients carried 1 of 2 splice site mutations on 1 allele, predicted to result in premature termination and a loss of function, whereas the other allele was either a missense mutation or an in-frame deletion, postulated to have some residual activity as a hypomorphic allele. Patient fibroblasts showed decreased levels of RINT1 protein compared to controls and abnormal Golgi morphology with increased fragmentation, suggestive of a trafficking defect. There was also increased cytoplasmic LC3 (601242), suggesting a decrease in autophagosome clearance.
Lin et al. (2007) found that homozygous deletion of Rint1 was lethal at embryonic day 5 to 6 in mouse and caused failure of blastocyst outgrowth ex vivo. Approximately 81% of Rint1 +/- mice succumbed to tumors in various organs during an average life span of 24 months.
In 2 unrelated patients (patients 1 and 3) with infantile liver failure syndrome-3 (ILFS3; 618641), Cousin et al. (2019) identified compound heterozygous mutations in the RINT1 gene. Both patients carried a G-to-A transition in intron 9 (c.1333+1G-A, NM_021930) that was demonstrated in patient cells to result in a splice site defect, the skipping of exon 9, and a frameshift leading to premature termination and nonsense-mediated mRNA decay. Each patient carried a different mutation on the other allele: patient 1 had an in-frame 6-bp deletion (c.1853_1858del6; 610089.0002) in exon 12, resulting in the deletion of 2 conserved residues (Val618_Lys619del), and patient 3 had a c.1109T-C transition in exon 9, resulting in a leu370-to-pro (L370P; 610089.0003) substitution at a conserved residue. The nucleotide substitution leading to the L370P mutation was given as c.1109C-T in the text of the paper. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient fibroblasts showed decreased levels of RINT1 protein compared to controls, abnormal Golgi morphology suggestive of a trafficking defect, and increased cytoplasmic LC3 (601242), suggesting a decrease in autophagosome clearance.
For discussion of the in-frame 6-bp deletion in exon 12 of the RINT1 gene (c.1853_1858del6, NM_021930), resulting in the deletion of 2 conserved residues (Val618_Lys619del), that was found in compound heterozygous state in a patient with infantile liver failure syndrome-3 (ILFS3; 618641) by Cousin et al. (2019), see 610089.0001.
For discussion of the c.1109T-C transition (c.1109T-C, NM_021930) in exon 9 of the RINT1 gene, resulting in a leu370-to-pro (L370P) substitution, that was found in compound heterozygous state in a patient with infantile liver failure syndrome-3 (ILFS3; 618641) by Cousin et al. (2019), see 610089.0001.
In an 8-year-old girl of East Asian descent (patient 2) with infantile liver failure syndrome-3 (ILFS3; 618641), Cousin et al. (2019) identified compound heterozygous mutations in the RINT1 gene: a G-to-T transversion in intron 9 (c.1333+1G-T, NM_021930), predicted to result in a splice site defect, the skipping of exon 9, a frameshift, and premature termination, and a c.1102G-A transition in exon 8, resulting in an ala368-to-thr (A368T; 610089.0005) substitution at a conserved residue. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1102G-A transition (c.1102G-A, NM_021930) in exon 8 of the RINT1 gene, resulting in an ala368-to-thr (A368T) substitution, that was found in compound heterozygous state in a patient with infantile liver failure syndrome-3 (ILFS3; 618641) by Cousin et al. (2019), see 610089.0001.
Arasaki, K., Takagi, D., Furuno, A., Sohda, M., Misumi, Y., Wakana, Y., Inoue, H., Tagaya, M. A new role for RINT-1 in SNARE complex assembly at the trans-Golgi network in coordination with the COG complex. Molec. Biol. Cell 24: 2907-2917, 2013. [PubMed: 23885118] [Full Text: https://doi.org/10.1091/mbc.E13-01-0014]
Cousin, M. A., Conboy, E., Wang, J.-S., Lenz, D., Schwab, T. L., Williams, M., Abraham, R. S., Barnett, S., El-Youssef, M., Graham, R. P., Gutierrez Sanchez, L. H., Hasadsri, L., and 17 others. RINT1 bi-allelic variations cause infantile-onset recurrent acute liver failure and skeletal abnormalities. Am. J. Hum. Genet. 105: 108-121, 2019. [PubMed: 31204009] [Full Text: https://doi.org/10.1016/j.ajhg.2019.05.011]
Kong, L.-J., Meloni, A. R., Nevins, J. R. The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Molec. Cell 22: 63-71, 2006. [PubMed: 16600870] [Full Text: https://doi.org/10.1016/j.molcel.2006.02.016]
Lin, X., Liu, C.-C., Gao, Q., Zhang, X., Wu, G., Lee, W.-H. RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival. Molec. Cell. Biol. 27: 4905-4916, 2007. [PubMed: 17470549] [Full Text: https://doi.org/10.1128/MCB.02396-06]
Xiao, J., Liu, C.-C., Chen, P.-L., Lee, W.-H. RINT-1, a novel Rad50-interacting protein, participates in radiation-induced G2/M checkpoint control. J. Biol. Chem. 276: 6105-6111, 2001. [PubMed: 11096100] [Full Text: https://doi.org/10.1074/jbc.M008893200]