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HAX1
HCLS1 associated protein X-1
The HAX1 gene encodes the HAX-1 protein, which plays a role in regulating programmed cell death (apoptosis) and cellular movement within the body. The HAX1 gene provides instructions for making the HS-1-associated protein X-1 (HAX-1), a protein primarily located in the mitochondria.
HAX1 is located on the long (q) arm of chromosome 1, at band 1q21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The HAX1 gene, or HCLS1 associated protein X-1, is central to several fundamental cellular processes. It produces a protein known as HAX-1, which is found predominantly in the mitochondria, the energy-producing organelles within cells. The HAX-1 protein is critical for regulating apoptosis, the body's mechanism for removing damaged or unnecessary cells, and contributes to cell movement.
What the gene does
The HAX-1 protein, encoded by the HAX1 gene, functions as a regulator of apoptosis, a crucial process where cells self-destruct when they are damaged or no longer needed. Beyond its role in programmed cell death, HAX-1 is also believed to be involved in cellular migration and movement. Different versions of the HAX-1 protein can be produced through alternative splicing of the HAX1 gene, though the specific functions of these multiple forms are not yet fully understood. These different protein forms may allow for diverse roles in various cellular contexts.
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Chromosome location
The HAX1 gene is situated on chromosome 1 at position 1q21.3. This genomic location indicates its specific address within the human genome, where it provides the blueprint for the HAX-1 protein.
Protein structure
The HAX-1 protein consists of 279 amino acids. Key regions include amino acids 2-41, which are required for its localisation in mitochondria, and regions from amino acids 16-65 and 99-262, which are characterised as disordered. The protein is involved in binding with HCLS1 (amino acids 114-279), CASP9 (amino acids 175-206), and GNA13 (amino acids 176-247). A region spanning amino acids 183-279 is required for localisation in the sarcoplasmic reticulum, and this same extended region (amino acids 184-279) is involved in PKD2 binding. Further interactions include ATP2A2 binding (amino acids 203-245), PLN binding (amino acids 203-225), and mediation of interaction with UCP3 (amino acids 210-279). Amino acids 270-279 are specifically required for ITGB6 binding.
Key variants
Variants within the HAX1 gene can alter the function of the HAX-1 protein. Such genetic changes may impact the protein's ability to regulate apoptosis or its role in cell migration, leading to various health implications. The specific consequences depend on the nature and location of the variant within the gene.
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.109G>T | p.Glu37Ter | Pathogenic/Likely pathogenic | ★★☆☆ | HAX1-related disorder |
c.337G>T | p.Glu113Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Kostmann syndrome |
c.368_381del | p.Gln123fs | Pathogenic | ★★☆☆ | Kostmann syndrome |
c.383C>G | p.Ser128Ter | Pathogenic | ★★☆☆ | Kostmann syndrome |
c.407del | p.His136fs | Pathogenic/Likely pathogenic | ★★☆☆ | HAX1-related disorders |
c.430dup | p.Val144fs | Pathogenic | ★★☆☆ | Kostmann syndrome |
c.463dup | p.Gln155fs | Pathogenic/Likely pathogenic | ★★☆☆ | HAX1-related disorders |
c.557-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Kostmann syndrome |
c.663+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Kostmann syndrome |
c.85C>T | p.Arg29Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Kostmann syndrome |
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 HAX1 gene are associated with inherited conditions, most notably Severe congenital neutropenia (Kostmann). This condition is characterised by a deficiency of neutrophils, a type of white blood cell vital for fighting infections. Most of the HAX1 gene variants linked to Severe congenital neutropenia involve changes to single amino acid building blocks in the HAX-1 protein.
- Severe congenital neutropenia (Kostmann) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic HAX1 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 HAX1 gene is recognised in the UK's NHS Genomic Medicine Service, being listed on several PanelApp panels. These include "COVID-19 research," "Cytopenia - NOT Fanconi anaemia," "Cytopenias and congenital anaemias," "DDG2P," "Early onset or syndromic epilepsy," "Haematological malignancies cancer susceptibility," "Haematological malignancies for rare disease," and "Primary immunodeficiency or monogenic inflammatory bowel disease."
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the HAX1 gene?
The HAX1 gene provides instructions for the HAX-1 protein, which is primarily involved in regulating apoptosis (programmed cell death) and is also thought to play a role in cell movement.
Which condition is associated with HAX1 gene variants?
Variants in the HAX1 gene are associated with Severe congenital neutropenia, a condition characterised by a shortage of neutrophils, which are a type of white blood cell important for the immune system.
Where is the HAX-1 protein mainly found in cells?
The HAX-1 protein is found predominantly in the mitochondria, which are often referred to as the 'powerhouses' of the cell due to their role in energy production.
References
- Zeidler C, Germeshausen M, Klein C. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia. British journal of haematology. 2009. PMID: 19120359
- Fadeel B, Grzybowska E. HAX-1: a multifunctional protein with emerging roles in human disease. Biochimica et biophysica acta. 2009. PMID: 19524642
- Xia J, Bolyard AA, Rodger E. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. British journal of haematology. 2009. PMID: 19775295
- Boztug K, Klein C. Novel genetic etiologies of severe congenital neutropenia. Current opinion in immunology. 2009. PMID: 19782549