On this page
ITPR1
inositol 1,4,5-trisphosphate receptor type 1
The ITPR1 gene provides instructions for a protein that forms part of a channel regulating calcium ion flow within cells, crucial for the proper function of various tissues and organs. The ITPR1 gene encodes the inositol 1,4,5-trisphosphate receptor type 1 protein, which plays a vital role in controlling intracellular calcium signalling.
ITPR1 is located on the short (p) arm of chromosome 3, at band 3p26.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 3 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The ITPR1 gene, or inositol 1,4,5-trisphosphate receptor type 1, is integral to cellular communication and function. It provides the genetic blueprint for a protein that acts as a calcium channel within cells. This channel is crucial for maintaining appropriate calcium concentrations, which in turn influences a wide array of biological processes, from nerve impulse transmission to muscle contraction and gene expression.
Disruptions in the ITPR1 gene's function can lead to various neurological disorders, particularly those affecting coordination and development. Understanding the role of ITPR1 is key to comprehending the underlying mechanisms of these conditions.
What the gene does
The ITPR1 gene produces a protein that is a fundamental component of calcium channels located within the endoplasmic reticulum membrane. Four ITPR1 protein molecules typically come together to form a functional channel, known as a homotetramer. Upon receiving specific cellular signals, this channel facilitates the controlled release of calcium ions from the endoplasmic reticulum, where they are stored, into the surrounding cytoplasm.
This precise regulation of intracellular calcium concentration is paramount for numerous cellular activities. It contributes to signal transduction pathways, neuronal excitability, synaptic plasticity, and the overall development and maintenance of diverse tissues and organs. Alterations in this calcium regulation can have significant consequences for cellular health and systemic physiological processes.
Video: Genetics 101
Chromosome location
The ITPR1 gene is located on the long arm of chromosome 3 at position 3p26.1. This specific genomic address helps to precisely map its location within the human genome. The gene's position is consistent across individuals.
Protein structure
The ITPR1 protein is relatively large, consisting of 2758 amino acids. It features several distinct molecular recognition (MIR) domains, specifically 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 several intrinsically disordered regions at various positions, including amino acids 1015-1036, 1146-1178, 1708-1740, 1760-1796, 1890-1915, 1939-1960, and 2729-2758. A specific region between amino acids 2472-2537 is involved in interaction with the ERP44 protein.
Key variants
Variants in the ITPR1 gene can alter the protein's structure or function, impacting the precise control of calcium ion flow within cells. These genetic changes can range from small sequence alterations to larger deletions or duplications. The specific type and location of a variant often influence the severity and presentation of associated conditions.
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 | ★★☆☆ | Spinocerebellar ataxia type 29 |
c.1781C>T | p.Thr594Ile | Pathogenic | ★★☆☆ | Spinocerebellar ataxia type 15/16 |
c.3261_3262del | p.Ala1089fs | Pathogenic/Likely pathogenic | ★★☆☆ | Gillespie syndrome |
c.6325G>A | p.Glu2109Lys | Pathogenic/Likely pathogenic | ★★☆☆ | ITPR1-related disorders |
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 |
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
Variants in the ITPR1 gene are associated with a spectrum of neurological conditions. Gillespie syndrome is linked to at least 13 identified ITPR1 gene variants, characterised by eye abnormalities, congenital hypotonia, ataxia, and mild to moderate intellectual disability. Additionally, ITPR1 variants have been implicated in spinocerebellar ataxia type 15 (SCA15) and spinocerebellar ataxia type 29 (SCA29), and other forms of spinocerebellar ataxia, all of which lead to progressive movement difficulties.
No disease links recorded for this gene in our reference set.
UK clinical status
The ITPR1 gene is included in several NHS England Genomic Medicine Service approved panels due to its clinical significance. It is classified as 'green' on panels related to Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, DDG2P, Hereditary ataxia, Hereditary ataxia (adult onset), Intellectual disability, and Sporadic aniridia.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ITPR1 gene do?
The ITPR1 gene provides instructions for making a protein that forms part of a channel in cell membranes. This channel controls the release of calcium ions from storage within the cell, which is essential for various cellular processes and functions.
What conditions are associated with variants in the ITPR1 gene?
Variants in the ITPR1 gene are associated with several neurological conditions, including Gillespie syndrome, spinocerebellar ataxia type 15 (SCA15), and spinocerebellar ataxia type 29 (SCA29). These conditions often involve problems with coordination, balance, and muscle tone.
How do ITPR1 gene variants affect calcium regulation?
ITPR1 gene variants can alter the structure or function of the protein, thereby impairing its ability to properly regulate the flow of calcium ions within cells. This disruption in calcium signalling can lead to the symptoms observed in associated neurological disorders.
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