Alternative titles; symbols
HGNC Approved Gene Symbol: RIMS2
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:103,500,610-104,256,094 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.3 | Cone-rod synaptic disorder syndrome, congenital nonprogressive | 618970 | Autosomal recessive | 3 |
For background information on RIM proteins, see RIM1 (606629).
By screening for cDNAs with the potential to encode large proteins expressed in brain, Nagase et al. (1998) identified a cDNA encoding RIM2, which they called KIAA0751. The deduced 1,188-amino acid protein was predicted to be related to RIM1 and to be involved in cell signaling/communication. RT-PCR analysis detected high expression of KIAA0751 in brain, with lower expression in ovary and testis.
Wang and Sudhof (2003) stated that the full-length RIM2 protein, which they designated RIM2-alpha, contains an N-terminal zinc-binding domain, followed by a PDZ domain, a C2A domain, a PxxP motif, and a C-terminal C2B domain. They identified RIM2 splice variants encoding RIM2-beta, which has a short unique sequence instead of the N-terminal zinc-binding domain, and RIM2-gamma, which lacks all the domains of RIM2-alpha except the C-terminal C2B domain and flanking sequences.
Mechaussier et al. (2020) analyzed human adult neural retina datasets and found that RIMS2 is predominantly expressed in rod photoreceptor clusters. RT-qPCR analysis of human fetal tissues with primers specific for each of the 3 RIMS2 isoforms, RIMS2-alpha, -beta, and -gamma, showed that all transcripts were expressed far more highly in the brain than in other tissues. In the retina, the 3 transcripts seemed equally expressed. In the pancreas, RIMS2-gamma had the highest expression, followed by RIMS2-alpha, then RIMS2-beta, whereas RIMS2-alpha expression was undetectable in fibroblasts, which showed predominant RIMS2-gamma expression. The authors immunostained for RIMS2-alpha and -beta isoforms in adult human retina, brain, and pancreas, and observed strong and specific immunostaining in the outer plexiform retinal layer, in the Purkinje cells of the cerebellar cortex, and in the pancreatic Langerhans islets.
Wang and Sudhof (2003) determined that the RIMS2 gene contains 32 exons and spans 747.9 kb. In addition to the 5-prime promoter region, RIMS2 has 2 internal promoters within GC-rich regions that are used for expression of RIM2-beta and RIM2-gamma.
By genomic sequence analysis, Wang and Sudhof (2003) mapped the RIMS2 gene to human chromosome 8q23 and to mouse chromosome 5A2.
Stumpf (2020) mapped the RIMS2 gene to chromosome 8q22.3 based on an alignment of the RIMS2 sequence (GenBank BC043144) with the genomic sequence (GRCh38).
Wang et al. (2000) demonstrated that rat Rim2 interacted with Rab3a (179490) and Rab3c in a GTP-dependent manner. Yeast 2-hybrid analysis of a rat brain cDNA library revealed that the C-terminal half of rat Rim2 interacted with Rimbp1 (BZRAP1; 610764) and Rimbp2 (611602).
Lohner et al. (2017) identified Rim2 as the major large RIM isoform present at mouse sensory photoreceptor ribbon synapses. Mouse photoreceptors predominantly expressed Rim2 isoforms lacking the N-terminal zinc finger domain and part of the Rab3a-binding domain, leading to loss of Rim2 interaction with Munc13-2 (UNC13B; 605836) and to decreased or absence of Rab3a binding. However, absence of full-length Rim2 only marginally perturbed photoreceptor synaptic transmission in mice. The authors concluded that the role of Rim2 at photoreceptor ribbon synapses is different from RIM function in most other types of chemical synapses. They proposed that at the photoreceptor ribbon synaptic active zone, Rim2 is not essential for vesicle priming or Ca(2+) channel clustering, but instead acts as a Ca(2+) channel modulator.
In 7 patients from 4 unrelated families with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970), Mechaussier et al. (2020) identified homozygosity or compound heterozygosity for mutations in the RIMS2 gene (606630.0001-606630.0005) that segregated fully with disease in each family.
By analyzing mice with conditional double knockout of Rim1 and Rim2 at the calyx of Held synapse, Han et al. (2011) showed that Rim1 and Rim2 enriched voltage-gated Ca(2+) channels at the presynaptic nerve terminal and thereby determined presynaptic Ca(2+) channel density. Rim1 and Rim2 ensured the presence of a large readily releasable vesicle pool and influenced the release probability of those vesicles. Specifically, Rim1 and Rim2 determined the size of the readily releasable pool and increased the intracellular Ca(2+) sensitivity of release by contributing to coupling between Ca(2+) channels and readily releasable vesicles. Furthermore, Rim1 and Rim2 coordinated vesicle docking to the presynaptic active zone.
In a mother, son, and the mother's sister from a consanguineous Senegalese family (family 1) with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970), Mechaussier et al. (2020) identified homozygosity for a c.3126G-A transition (c.3126G-A, NM_001348484.1) in the RIMS2 gene, resulting in a trp1042-to-ter (W1042X) substitution. The mutation segregated with disease in the family. Immunoblot analysis in HEK293 cells overexpressing the W1042X mutant confirmed production of an approximately 130-kD truncated protein, compared to the approximately 210-kD wildtype protein. MIN6B1 cells overexpressing the W1042X mutant showed reduced insulin accumulation, whereas overexpression of wildtype RIMS2 did not affect insulin secretion.
In a 7-year-old French boy (family 2) with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970), Mechaussier et al. (2020) identified compound heterozygosity for a c.2884C-T transition (c.2884C-T, NM_001348484.1) in the RIMS2 gene, resulting in an arg962-to-ter (R962X) substitution, and a splicing mutation (c.4363+1G-A) in intron 29, predicted to abolish the donor splice site and cause skipping of the adjacent exon (c.4251_4363del), resulting in a frameshift and introduction of a premature termination codon (Asn1417LysfsTer2). His unaffected parents were each heterozygous for 1 of the mutations. Immunoblot analysis in HEK293 cells overexpressing the R962X mutant confirmed production of an approximately 120-kD truncated protein, compared to the approximately 210-kD wildtype protein. MIN6B1 cells overexpressing the R962X mutant showed reduced insulin accumulation, whereas overexpression of wildtype RIMS2 did not affect insulin secretion.
For discussion of the splicing mutation (c.4363+1G-A, NM_001348484.1) in intron 29 of the RIMS2 gene, that was found in compound heterozygous state in a 7-year-old French boy (family 2) with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970) by Mechaussier et al. (2020), see 606630.0002.
In a 7-year-old boy and his 6-year-old sister, born of consanguineous Saudi Arabian parents (family 3), with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970), Mechaussier et al. (2020) identified homozygosity for a c.3508C-T transition (c.3508C-T, NM_001348484.1) in the RIMS2 gene, resulting in an arg1170-to-ter (R1170X) substitution. Their unaffected parents were heterozygous for the mutation. Immunoblot analysis in HEK293 cells overexpressing the R1170X mutant confirmed production of an approximately 150-kD truncated protein, compared to the approximately 210-kD wildtype protein. MIN6B1 cells overexpressing the R1170X mutant showed reduced insulin accumulation, whereas overexpression of wildtype RIMS2 did not affected insulin secretion.
In a 9-year-old Senegalese boy with congenital nonprogressive cone-rod synaptic disorder syndrome (CRSDS; 618970), Mechaussier et al. (2020) identified homozygosity for a c.1595C-G transversion in the RIMS2 gene, resulting in a ser532-to-ter (S532X) substitution. His consanguineous parents were heterozygous for the mutation. Immunoblot analysis in HEK293 cells overexpressing the S532X mutant confirmed production of an approximately 60-kD truncated protein, compared to the approximately 210-kD wildtype protein.
Han, Y., Kaeser, P. S., Sudhof, T. C., Schneggenburger, R. RIM determines Ca(2+) channel density and vesicle docking at the presynaptic active zone. Neuron 69: 304-316, 2011. [PubMed: 21262468] [Full Text: https://doi.org/10.1016/j.neuron.2010.12.014]
Lohner, M., Babai, N., Muller, T., Gierke, K., Atorf, J., Joachimsthaler, A., Peukert, A., Martens, H., Feigenspan, A., Kremers, J., Schoch, S., Helmut Brandstatter, J., Regus-Leidig, H. Analysis of RIM expression and function at mouse photoreceptor ribbon synapses. J. Neurosci. 37: 7848-7863, 2017. [PubMed: 28701482] [Full Text: https://doi.org/10.1523/JNEUROSCI.2795-16.2017]
Mechaussier, S., Almoallem, B., Zeitz, C., Van Schil, K., Jeddawi, L., Van Dorpe, J., Duenas Rey, A., Condroyer, C., Pelle, O., Polak, M., Boddaert, N., Bahi-Buisson, N., and 10 others. Loss of function of RIMS2 causes a syndromic congenital cone-rod synaptic disease with neurodevelopmental and pancreatic involvement. Am. J. Hum. Genet. 106: 859-871, 2020. Note: Erratum: Am. J. Hum. Genet. 107: 580 only, 2020. [PubMed: 32470375] [Full Text: https://doi.org/10.1016/j.ajhg.2020.04.018]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/29/2020.
Wang, Y., Sudhof, T. C. Genomic definition of RIM proteins: evolutionary amplification of a family of synaptic regulatory proteins. Genomics 81: 126-137, 2003. [PubMed: 12620390] [Full Text: https://doi.org/10.1016/s0888-7543(02)00024-1]
Wang, Y., Sugita, S., Sudhof, T. C. The RIM/NIM family of neuronal C2 domain proteins: interactions with Rab3 and a new class of Src homology 3 domain proteins. J. Biol. Chem. 275: 20033-20044, 2000. [PubMed: 10748113] [Full Text: https://doi.org/10.1074/jbc.M909008199]