The RIMS2 gene encodes a large cellular protein consisting of an N-terminal zinc-binding domain, a PDZ domain, a C2A domain, a PxxP motif and a C-terminal C2B domain. While the protein is yet to be fully characterized, its potential role has been inferred through lower ortholog studies. RIMS2 has thus been suggested to function as a Rab effector involved in exocytosis, particularly synaptic membrane exocytosis and calcium ion-regulated exocytosis of neurotransmitter. It is also believed to function in the biological processes of cAMP mediated signaling, insulin secretion, regulation of dendrite extension, regulation of excitatory/inhibitory postsynaptic potential and spontaneous neurotransmitter secretion.
The RIMS2 gene is located on the long arm of chromosome 8. It spans a length of 755.4 kb of DNA and its coding sequence is spread across 39 exons. The gene encodes a 160 kDa protein product composed of 1411 amino acids. Several additional isoforms of the RIMS2 protein exist due to alternatively spliced transcript variants. While the gene is highly expressed in the brain, lower expression is also seen in the adrenal gland, ovary and testis.
Monies et al. (2017) investigated the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, a 6-year-old female, presented with lower limb muscle weakness and spasticity with periventricular leukomalacia. Tests revealed that she had normal levels of serum creatine kinase. Whole exome sequencing helped identify a heterozygous mutation (c.418C>T, p.R140C) in exon 2 of the patient’s RIMS2 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel variant predicted to be deleterious; and the RIMS2 gene has an established role in synapse formation. Further, the gene has a pLI score of 1.0, indicating that it was highly likely to be intolerant of loss-of-function mutations. The authors noted the need for independent confirmation of this association.