The ITPR1 gene encodes the receptor for inositol 1,4,5-triphosphate, a messenger produced by phospholipase C. The ITPR1 receptor is an intracellular ligand-gated calcium channel, and upon activation by inositol 1,4,5-triphosphate, it mediates the release of calcium ions from the endoplasmic reticulum. By carrying out its function, ITPR1 plays a role in calcium-mediated signaling, ER-stress induced apoptosis, platelet activation, insulin secretion and cardiac conduction.
The ITPR1 protein consists of a transmembrane domain near the C terminal, an inositol triphosphate binding domain near the N terminal and a coupling domain in the middle of the molecule. It also consists of at least 2 consensus protein kinase A phosphorylation sites and at least 1 consensus ATP-binding site. The gene has been associated with Spinocerebellar Ataxia 15 (SCA15, autosomal dominant), Spinocerebellar Ataxia 29 (SCA29) and Gillespie Syndrome.
ITPR1 is located on the p arm of chromosome 3 and is 354,493 bases long, ranging from 4,493,348 to 4,847,840 base pairs pter. It contains 61 exons and translates into a 2,758aa long protein with a molecular weight of 313,929 Da. ITPR1 mRNA is ubiquitously expressed, and is thought to translate locally in neuronal cells through cis and trans effectors in response to synaptic activity. Protein is widely expressed and exists in multiple isoforms with one isoform mainly functioning in the brain; peripheral protein expression is most abundant in blood mononuclear cells, urine, lung alveolar lavage, and colon. 8 possible alternatively spliced isoforms and 5 paralogs have been identified. ITPR1 exhibits an N-terminal ligand binding (inositol triphosphate) domain, coupling and modulatory domain, a C-terminal multi-pass transmembrane (calcium channel) domain, as well as kinase phosphorylation and ATP-binding sites. Inositol triphosphate binds and homotetramerizes ITPR1 and mediates the flow of Ca+2 ions from endoplasmic reticulum, cytosolic, or vesicular calcium stores.
ITPR1 haploinsufficiency is associated with multiple autosomal dominant disorders. Large heterozygous deletions in ITPR1 are mainly associated with spinocerebellar ataxia 15 (SCA15); heterozygous missense mutations are associated with spinocerebellar ataxia 29 (SCA29), as well as rare cases of SCA15. Heterozygous missense and in frame deletion mutations are associated with Gillespie Syndrome.
Monies et al. (2017) discussed the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 7-year-old female, presented with global developmental delay and brain atrophy. Using a multigene panel for neurological disorders, a homozygous mutation (c.6862C>T, p.R2288X) was identified in exon 50 of the patient’s ITPR1 gene. Hence this case presented an interesting finding of a recessive mutation in a gene normally associated with a dominant phenotype (SCA15). Further, the atypical presentation of the patient helped expand the phenotype of SCA15.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient was diagnosed with spinocerebellar ataxia 15 (SCA15). A heterozygous missense transversion in ITPR1 (c.3758T>A, p.Iso1253Asn) was identified as the probable cause. A second heterozygous missense transversion in MYH14 (c.1126G>T; p.Gly376Cys), associated with autosomal dominant deafness 4A (DFNA4a), was also identified; however the patient did not exhibit symptoms of the latter disorder.
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