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NEB
nebulin
The NEB gene encodes the nebulin protein, a critical component of skeletal muscle sarcomeres essential for muscle contraction and force generation. Nebulin plays a fundamental role in maintaining the structural integrity and proper function of skeletal muscles, which are responsible for voluntary movement.
NEB is located on the long (q) arm of chromosome 2, at band 2q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NEB gene provides the genetic blueprint for a protein called nebulin, which is predominantly expressed in skeletal muscles. These muscles are responsible for controlling voluntary movements throughout the body. Nebulin is a crucial structural protein within muscle cells, contributing to the assembly and stability of sarcomeres, which are the repeating units enabling muscle fibres to generate force during contraction [PMID:19307323].
Dysfunction of the nebulin protein, often due to pathogenic variants in the NEB gene, can impair muscle contraction and lead to various muscle-related disorders, including a form of nemaline myopathy. Understanding the role of NEB is important for diagnosing and researching inherited muscle conditions.
What the gene does
The nebulin protein is an integral part of the skeletal muscle sarcomere, specifically located within the thin filaments. Sarcomeres are highly organised structures that enable muscle cells to contract, producing the mechanical force necessary for movement. Nebulin acts as a molecular ruler, helping to regulate the length of the actin thin filaments within the sarcomere, which is critical for optimal muscle contraction efficiency [PMID:16049216].
Beyond its role in thin filament length regulation, nebulin interacts with several other proteins within the sarcomere, contributing to its overall structural integrity and mechanical properties. This intricate network of interactions ensures that muscle fibres can contract efficiently and maintain their architecture under stress. Disruptions to nebulin's structure or expression due to NEB gene variants can compromise these vital functions, leading to muscle weakness and impaired movement.
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Chromosome location
The NEB gene is situated on the long arm of chromosome 2, specifically at position 2q23.3. This chromosomal location indicates where the gene can be found within the human genome.
Protein structure
The nebulin protein has a substantial length, consisting of 8525 amino acid residues. Its architecture includes a Disordered region at amino acids 34-70, followed by a series of Nebulin Repeats. These include Nebulin 1 (83-110), Nebulin 2 (112-146), Nebulin 3 (156-181), Nebulin 4 (182-216), Nebulin 5 (217-251), Nebulin 6 (252-286), Nebulin 7 (296-321), Nebulin 8 (323-357), Nebulin 9 (362-396), Nebulin 10 (403-431), Nebulin 11 (433-467), Nebulin 12 (501-535), Nebulin 13 (536-570), and Nebulin 14 (572-606). These repetitive domains are key to nebulin's function as a structural protein within muscle sarcomeres.
Key variants
Variants in the NEB gene can take various forms, including alterations affecting individual amino acid residues, or the addition or removal of DNA sequences. These genetic alterations can lead to the production of truncated nebulin molecules or affect the protein's normal architecture, ultimately compromising its ability to function correctly within muscle cells [PMID:19188035]. More than 60 different pathogenic variants in the NEB gene have been identified as causes of nemaline myopathy.
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.11628G>A | p.Trp3876Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Nemaline myopathy |
c.12166del | p.Thr4056fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nemaline myopathy |
c.1263dup | p.Tyr422fs | Pathogenic | ★★☆☆ | Arthrogryposis multiplex congenita 6 |
c.18187C>T | p.Arg6063Ter | Pathogenic | ★★☆☆ | Nemaline myopathy 2 |
c.18372dup | p.Tyr6125fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nemaline myopathy 2 |
c.1978C>T | p.Gln660Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Nemaline myopathy 2 |
c.2559del | p.Lys854_Met855insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Nemaline myopathy 2 |
c.5349_5350del | p.Tyr1784fs | Pathogenic/Likely pathogenic | ★★☆☆ | Arthrogryposis multiplex congenita 6 |
c.82del | p.Thr27_Ile28insTer | Pathogenic/Likely pathogenic | ★★☆☆ | NEB-related disorder |
c.9974G>A | p.Trp3325Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Arthrogryposis multiplex congenita 6 |
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 NEB gene are primarily associated with Nemaline myopathy. This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two altered copies of the gene (one from each parent) to develop the condition. Nemaline myopathy is characterised by muscle weakness, often presenting with symptoms such as poor muscle tone (hypotonia) and feeding difficulties in infancy.
Inheritance pattern
Conditions caused by pathogenic NEB 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 NEB gene is recognised within the NHS Genomic Medicine Service. It is listed with a 'green' status on NHS England's PanelApp for several conditions, including Arthrogryposis (R83), Congenital myopathy (R81), DDG2P, Distal myopathies, and Foetal anomalies (R21). A 'green' status indicates that there is sufficient evidence for NEB to be considered a strong candidate gene for these conditions in a diagnostic setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NEB gene?
The NEB gene provides instructions for making nebulin, a protein crucial for the structure and function of skeletal muscles. It helps regulate the length of muscle filaments, which is essential for muscle contraction.
What condition is associated with NEB gene variants?
Variants in the NEB gene are primarily associated with Nemaline myopathy, an inherited disorder characterised by muscle weakness and poor muscle tone, typically affecting skeletal muscles.
How is Nemaline myopathy inherited?
Nemaline myopathy caused by NEB gene variants is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
References
- Ottenheijm CA, Hooijman P, DeChene ET. Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2). Journal of structural biology. 2010. PMID: 19944167
- Lehtokari VL, Pelin K, Sandbacka M. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Human mutation. 2006. PMID: 16917880
- Ryan MM, Schnell C, Strickland CD. Nemaline myopathy: a clinical study of 143 cases. Annals of neurology. 2001. PMID: 11558787