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ITPR1
inositol 1,4,5-trisphosphate receptor type 1
The ITPR1 gene provides instructions for producing a protein essential for controlling calcium ion release within cells, a process vital for proper tissue and organ function. ITPR1 is responsible for creating a protein that forms part of an intracellular channel, regulating calcium movement from storage sites into the cell's cytoplasm.
ITPR1 is located on the short (p) arm of chromosome 3, at band 3p26.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ITPR1 gene, or inositol 1,4,5-trisphosphate receptor type 1, is crucial for maintaining cellular calcium homeostasis. It encodes a protein that acts as a calcium release channel, primarily located on the endoplasmic reticulum membrane.
Precise control over intracellular calcium levels is fundamental for numerous physiological processes, including nerve impulse transmission, muscle contraction, and cell signalling. Pathogenic variants in ITPR1 are associated with several neurological conditions, reflecting its critical role in brain development and function.
What the gene does
The ITPR1 gene encodes the inositol 1,4,5-trisphosphate receptor type 1 protein, which is a key component of calcium ion channels within cells. These channels are typically formed by four ITPR1 protein molecules assembling into a complex known as a homotetramer. Upon specific cellular signals, the ITPR1 channel facilitates the release of calcium ions from internal storage compartments, such as the endoplasmic reticulum, into the surrounding cytoplasm. This controlled release of calcium is fundamental for a wide array of cellular activities and processes. Maintaining appropriate calcium concentrations inside cells is vital for the normal development and functioning of various tissues and organs throughout the body.
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Chromosome location
The ITPR1 gene is located on the short arm of chromosome 3, specifically at position 3p26.1. This genomic location places ITPR1 within a region that has been linked to several neurological disorders. The precise positioning on the chromosome helps in understanding its genetic context and potential interactions with neighbouring genes.
Protein structure
The ITPR1 protein is comprised of 2758 amino acids and features several distinct domains and regions. It includes five MIR domains: MIR 1 (amino acids 112-166), MIR 2 (amino acids 173-223), MIR 3 (amino acids 231-287), MIR 4 (amino acids 294-373), and MIR 5 (amino acids 379-435). Additionally, the protein contains multiple disordered regions, such as those at amino acids 1015-1036, 1146-1178, 1708-1740, 1760-1796, 1890-1915, 1939-1960, and 2729-2758. An important region for interaction with ERP44 is located between amino acids 2472-2537.
Key variants
Variants within the ITPR1 gene can lead to altered protein function, impacting its ability to regulate intracellular calcium levels. These genetic changes can range from single base-pair substitutions to larger deletions or duplications. The type and location of a variant often influence the severity and specific presentation of associated conditions. Understanding these variants is crucial for diagnosis and for informing clinical management.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1252-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1700A>G | p.Tyr567Cys | Pathogenic | ★★☆☆ | Gillespie syndrome |
c.1781C>T | p.Thr594Ile | Pathogenic | ★★☆☆ | Spinocerebellar ataxia type 15/16 |
c.3261_3262del | p.Ala1089fs | Pathogenic/Likely pathogenic | ★★☆☆ | Gillespie syndrome |
c.722G>A | p.Arg241Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Spinocerebellar ataxia type 29 |
c.731A>G | p.His244Arg | Pathogenic/Likely pathogenic | ★★☆☆ | not specified |
c.742_744del | p.Glu248del | Pathogenic/Likely pathogenic | ★★☆☆ | Spinocerebellar ataxia type 29 |
c.748T>C | p.Phe250Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Spinocerebellar ataxia type 15/16 |
c.800C>G | p.Thr267Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Spinocerebellar ataxia type 29 |
c.806G>T | p.Arg269Leu | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ITPR1 gene are implicated in several inherited neurological conditions. These include Gillespie syndrome, which presents with eye abnormalities, muscle hypotonia, ataxia, and intellectual disability. ITPR1 variants are also associated with various forms of spinocerebellar ataxia, such as spinocerebellar ataxia type 15 (SCA15) and spinocerebellar ataxia type 29 (SCA29), which are characterised by progressive problems with movement and coordination.
No disease links recorded for this gene in our reference set.
UK clinical status
The ITPR1 gene is included in several UK NHS national genomic testing panels, signifying its clinical importance in diagnosing inherited conditions. It is part of panels for 'Ataxia and cerebellar anomalies - childhood onset', 'Cerebellar hypoplasia', 'DDG2P', 'Hereditary ataxia', 'Hereditary ataxia, adult onset', 'Intellectual disability', and 'Sporadic aniridia'. Its presence on these green-rated panels indicates strong evidence for its role in these conditions within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ITPR1 gene?
The ITPR1 gene provides instructions for making a protein that forms part of a channel regulating the release of calcium ions from storage within cells into the cytoplasm. This precise control of calcium is vital for the proper function of many tissues and organs, especially in the nervous system.
What conditions are associated with changes in the ITPR1 gene?
Variants in the ITPR1 gene are linked to several neurological disorders, including Gillespie syndrome, which involves eye abnormalities, low muscle tone, and problems with coordination. It is also associated with types of spinocerebellar ataxia, such as SCA15 and SCA29, which cause progressive movement difficulties.
How does ITPR1 affect the brain?
ITPR1's role in controlling calcium levels is critical for brain development and function. Proper calcium signalling is essential for nerve cell communication, plasticity, and survival. Disruptions caused by ITPR1 variants can therefore lead to issues like intellectual disability, ataxia, and other neurological symptoms.
References
- Hall HN, Williamson KA, FitzPatrick DR. The genetic architecture of aniridia and Gillespie syndrome. Human genetics. 2019. PMID: 30242502
- Dentici ML, Barresi S, Nardella M. Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome. Gene. 2017. PMID: 28698159
- Gerber S, Alzayady KJ, Burglen L. Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome. American journal of human genetics. 2016. PMID: 27108797
- McEntagart M, Williamson KA, Rainger JK. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect. American journal of human genetics. 2016. PMID: 27108798