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HINT1
histidine triad nucleotide binding protein 1
The HINT1 gene provides instructions for making the histidine triad nucleotide binding protein 1, which is involved in nervous system function and programmed cell death. HINT1 is a gene that codes for a protein called histidine triad nucleotide binding protein 1.
HINT1 is located on the long (q) arm of chromosome 5, at band 5q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The HINT1 gene is responsible for producing the histidine triad nucleotide binding protein 1, often referred to simply as HINT1 protein. While its precise mechanisms are still being investigated, this protein is understood to have several roles within the body, particularly in the nervous system. Research suggests that HINT1 contributes to the regulation of nerve cell signalling and is involved in the process of programmed cell death.
Changes or variants within the HINT1 gene have been linked to specific neurological conditions. Understanding the function of HINT1 and how its variants can impact health is an active area of genetic research, especially concerning its role in inherited neuropathies.
What the gene does
The HINT1 gene provides the blueprint for the histidine triad nucleotide binding protein 1. Although its full functional scope is still under investigation, laboratory studies have indicated that the HINT1 protein has the capacity to bind to specific nucleotide molecules. It can also break down certain nucleotides through a process known as hydrolysis. However, it is not yet fully understood if these reactions occur in the same way within the human body or what their exact physiological effects are.
The HINT1 protein is also recognised for its involvement within the nervous system. Within neurons, HINT1 has been observed to bind to various signalling proteins, specifically receptors that facilitate nerve signal transmission. This binding activity appears to help stabilise the interactions between different receptors, thereby regulating the overall effects of their signalling pathways. Beyond its neural roles, HINT1 is also implicated in programmed cell death, a process by which cells are naturally removed when no longer needed. Additionally, HINT1 may function as a tumour suppressor by inhibiting the activity of certain genes, which could prevent cells from dividing and growing excessively.
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Chromosome location
The HINT1 gene is located on chromosome 5. Specifically, its chromosomal address is 5q23.3. This designation indicates that the gene resides on the long (q) arm of chromosome 5, within region 2, band 3, and sub-band 3. The HINT1 gene contains a single exon.
Protein structure
The HINT1 protein consists of 126 amino acids. It features a key structural element known as the HIT (histidine triad) domain, which spans amino acids 18 to 126. Within this larger HIT domain, there is a distinct histidine triad motif, located specifically at amino acids 110-114. This motif is characteristic of the HIT family of proteins and is crucial for the protein's ability to interact with nucleotides.
Key variants
Variants in the HINT1 gene can lead to alterations in the structure or function of the histidine triad nucleotide binding protein 1. These genetic changes can range from small alterations in the DNA sequence, such as single nucleotide changes, to larger deletions or insertions. Such variants can impact the protein's ability to bind nucleotides, participate in nerve cell signalling, or contribute to programmed cell death.
Many of the identified variants in HINT1 are considered pathogenic or likely pathogenic, meaning they are thought to cause or contribute to disease. The inheritance pattern associated with HINT1-related conditions is typically autosomal recessive, meaning an individual must inherit two copies of an altered gene (one from each parent) to develop the condition.
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.110G>C | p.Arg37Pro | Pathogenic | ★★☆☆ | HINT1-related disorders |
c.266G>T | p.Gly89Val | Pathogenic/Likely pathogenic | ★★☆☆ | Peripheral neuropathy |
c.278G>A | p.Gly93Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
c.316C>T | p.Gln106Ter | Pathogenic | ★★☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
c.334C>A | p.His112Asn | Pathogenic/Likely pathogenic | ★★☆☆ | HINT1-related disorders |
g.(?_131159273)_(131165358_?)del | - | Pathogenic | ★☆☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
g.(?_131159427)_(131165225_?)del | - | Pathogenic | ★☆☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
g.(?_130495140)_(130500898_?)del | - | Pathogenic | ★☆☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
g.(?_130500743)_(130501051_?)del | - | Pathogenic | ★☆☆☆ | Autosomal recessive axonal neuropathy with neuromyotonia |
c.100G>T | p.Glu34Ter | 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
Variants in the HINT1 gene have been linked to inherited neurological conditions, primarily autosomal recessive axonal neuropathy with neuromyotonia. This condition affects the peripheral nerves, which transmit signals between the brain, spinal cord, muscles, and sensory cells. Individuals with this neuropathy often experience muscle weakness, particularly in the feet, legs, and hands. It can also be associated with delayed muscle relaxation.
HINT1 variants are also discussed in the context of Charcot-Marie-Tooth disease, a group of inherited disorders that affect the peripheral nerves.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HINT1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HINT1 gene is recognised within the UK's genomic medicine initiatives, particularly within the NHS Genomic Medicine Service. It is listed on several green-rated panels in PanelApp, indicating strong evidence for its association with human disease. These include the DDG2P panel, the Hereditary neuropathy panel, and the Hereditary neuropathy or pain disorder panel (R78). This inclusion means that HINT1 is routinely considered in genetic testing for individuals suspected of having these neurological conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a generally healthy lifestyle is often recommended for individuals with genetic conditions, though specific lifestyle interventions for HINT1-related conditions are not well-established. This typically includes a balanced diet, regular physical activity as appropriate for individual capabilities, and avoiding excessive alcohol consumption. For individuals experiencing neuropathy, physical therapy and occupational therapy can be beneficial in managing symptoms and improving quality of life.
Supplement considerations
There is no conclusive evidence to suggest that specific dietary supplements can prevent, treat, or mitigate HINT1-related conditions. While some supplements are marketed for nerve health, their efficacy in genetically inherited neuropathies is not scientifically proven. Individuals considering any supplements should consult with a healthcare provider to discuss potential benefits, risks, and interactions with other medications or health conditions.
Frequently asked questions
What is the HINT1 gene?
The HINT1 gene provides instructions for making the histidine triad nucleotide binding protein 1. This protein is involved in various cellular processes, including nerve cell signalling and programmed cell death.
What conditions are associated with HINT1 gene variants?
Variants in the HINT1 gene are primarily associated with autosomal recessive axonal neuropathy with neuromyotonia, a neurological condition affecting peripheral nerves. It is also mentioned in the context of Charcot-Marie-Tooth disease.
How is HINT1-related neuropathy inherited?
HINT1-related conditions typically follow an autosomal recessive inheritance pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
What does the HINT1 protein do?
The HINT1 protein is believed to bind to nucleotides and break them down. In the nervous system, it helps regulate nerve cell signalling by interacting with receptors. It also plays a role in programmed cell death and may act as a tumour suppressor.
Is the HINT1 gene included in UK genetic testing panels?
Yes, the HINT1 gene is listed on several green-rated panels within the NHS Genomic Medicine Service's PanelApp, including those for hereditary neuropathy and developmental disorders.
References
- Zhao H, Race V, Matthijs G. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. European journal of human genetics : EJHG. 2014. PMID: 24105373
- Caetano JS, Costa C, Baets J. Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity. Pediatric neurology. 2014. PMID: 24131582
- Zhou X, Chou TF, Aubol BE. Kinetic mechanism of human histidine triad nucleotide binding protein 1. Biochemistry. 2013. PMID: 23614568
- Vicente-Sánchez A, Sánchez-Blázquez P, Rodríguez-Muñoz M. HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity. Molecular brain. 2013. PMID: 24093505
- Zimoń M, Baets J, Almeida-Souza L. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nature genetics. 2012. PMID: 22961002
- Rodríguez-Muñoz M, Sánchez-Blázquez P, Vicente-Sánchez A. The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor-glutamate NMDA receptor cross-regulation. Cellular and molecular life sciences : CMLS. 2011. PMID: 21153910
- Weiske J, Huber O. The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. The Journal of biological chemistry. 2006. PMID: 16835243
- Weiske J, Huber O. The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. Journal of cell science. 2005. PMID: 16014379