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NBEAL2
neurobeachin like 2
The NBEAL2 gene provides instructions for a protein crucial in the normal development and function of platelets, which are essential for blood clotting and wound healing. The NBEAL2 gene is responsible for producing a protein that plays a vital role in forming alpha-granules within megakaryocytes, the precursor cells to platelets.
NBEAL2 is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The NBEAL2 gene, also known as neurobeachin like 2, provides genetic instructions for a protein that is thought to be critical for the normal development of blood platelets. Platelets are small blood cells in the body that are essential for stopping bleeding through clot formation. Abnormalities in the NBEAL2 gene can lead to conditions characterised by impaired platelet function.
What the gene does
The NBEAL2 protein is primarily involved in the intricate process of platelet production, which originates in the bone marrow. Within megakaryocytes, the large precursor cells that give rise to platelets, the NBEAL2 protein is believed to be important for the formation of alpha-granules. Alpha-granules are the most abundant storage compartments within platelets, holding growth factors and other proteins that are vital for blood clotting and wound healing. When an injury occurs and causes bleeding, the proteins released from these alpha-granules assist platelets in aggregating to form a plug, sealing damaged blood vessels and preventing excessive blood loss.
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Chromosome location
The NBEAL2 gene is located on chromosome 3 at position 3p21.31. This specific genomic address helps to define its position within the human genome and is consistent across individuals.
Protein structure
The NBEAL2 protein is composed of 2754 amino acids. Its structure includes several key regions and domains. It features two disordered regions, one spanning amino acids 1298-1338 and another from 1364-1438. Further along, there is a BEACH-type PH domain (amino acids 1915-2040) and a larger BEACH domain (amino acids 2053-2345). The protein also contains multiple WD repeats: WD 1 (2386-2424), WD 2 (2448-2491), WD 3 (2494-2531), WD 4 (2544-2582), WD 5 (2589-2631), WD 6 (2639-2674), and WD 7 (2682-2717).
Key variants
Variants within the NBEAL2 gene can alter the protein's structure or function, impacting its role in platelet development. These changes can disrupt the formation or proper functioning of alpha-granules, leading to impaired blood clotting and other related symptoms. The specific impact of a variant depends on its nature and location 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.1789C>T | p.Arg597Ter | Pathogenic | ★★☆☆ | Gray platelet syndrome |
c.4081G>T | p.Glu1361Ter | Pathogenic | ★★☆☆ | NBEAL2-related disorder |
c.4485-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Gray platelet syndrome |
c.4485-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Gray platelet syndrome |
c.5476dup | p.Arg1826fs | Pathogenic | ★★☆☆ | Gray platelet syndrome |
g.(?_47021155)_(47021403_47030158)del | - | Pathogenic | ★☆☆☆ | Gray platelet syndrome |
c.2953C>T | p.Arg985Ter | Pathogenic | ★☆☆☆ | Gray platelet syndrome |
c.3222-2A>T | - | Pathogenic | ★☆☆☆ | Gray platelet syndrome |
c.5301+1G>A | - | Pathogenic | ★☆☆☆ | not provided |
c.925+5del | - | 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 NBEAL2 gene are primarily associated with inherited conditions affecting platelet function. The most notable condition linked to NBEAL2 is Gray platelet syndrome. This disorder typically manifests with abnormal bleeding tendencies and can also lead to myelofibrosis, a condition where scar tissue accumulates in the bone marrow, affecting the production of healthy blood cells.
Inheritance pattern
Conditions caused by pathogenic NBEAL2 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 NBEAL2 gene is included in several UK NHS national genomic testing panels. It is part of the 'Bleeding and platelet disorders' panel (R90) and the 'Inherited bleeding disorders' panel. This inclusion highlights its recognised role in diagnosing inherited conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NBEAL2 gene?
The NBEAL2 gene provides instructions for making a protein that is thought to be crucial for the normal development of platelets, which are essential for blood clotting and wound healing.
What is Gray platelet syndrome?
Gray platelet syndrome is an inherited disorder caused by variants in the NBEAL2 gene. It is characterised by abnormal bleeding due to impaired platelet function and can also involve the build-up of scar tissue in the bone marrow (myelofibrosis).
How does the NBEAL2 protein affect blood clotting?
The NBEAL2 protein is believed to be involved in forming alpha-granules within megakaryocytes, the cells that produce platelets. These alpha-granules store important proteins and growth factors necessary for platelets to effectively clot blood and heal wounds.
References
- Bottega R, Pecci A, De Candia E. Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency. Haematologica. 2013. PMID: 23100277
- Albers CA, Cvejic A, Favier R. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nature genetics. 2011. PMID: 21765411
- Gunay-Aygun M, Falik-Zaccai TC, Vilboux T. NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules. Nature genetics. 2011. PMID: 21765412
- Kahr WH, Hinckley J, Li L. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nature genetics. 2011. PMID: 21765413