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CHRNB1
cholinergic receptor nicotinic beta 1 subunit
CHRNB1 is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CHRNB1 gene encodes the beta-1 subunit of the muscle-type nicotinic acetylcholine receptor, a pentameric protein complex located at the neuromuscular junction. This receptor plays a critical role in converting chemical signals from motor neurons into electrical signals that trigger muscle contraction. When acetylcholine released from nerve terminals binds to the receptor, it opens an ion channel that allows sodium and potassium to flow across the muscle membrane, initiating the cascade that leads to muscle fibre contraction.
Biallelic pathogenic variants in CHRNB1 can impair receptor assembly or function, resulting in congenital myasthenic syndrome, a heterogeneous group of inherited disorders characterised by fatigable muscle weakness. The gene is included on NHS clinical panels for arthrogryposis, congenital myasthenic syndrome, and foetal anomalies, reflecting its importance in neuromuscular development and function.
What the gene does
The CHRNB1 protein combines with four other subunits (two alpha-1, one delta, and one epsilon or gamma subunit) to form the complete muscle nicotinic acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. This receptor acts as a ligand-gated ion channel, opening in response to acetylcholine binding and allowing rapid cation influx that depolarises the muscle membrane.
The beta-1 subunit contributes to the structural integrity of the receptor pentamer and influences receptor kinetics, including the speed of channel opening and closing. Proper assembly and localisation of the receptor complex require precise interactions between the beta-1 subunit and neighbouring subunits, as well as with anchoring proteins in the postsynaptic membrane. The receptor's function is essential for the rapid and reliable transmission of nerve impulses to muscle, enabling coordinated voluntary movement.
Dysfunction of the CHRNB1 protein can reduce the number of functional receptors at the neuromuscular junction or alter their response properties, compromising the safety margin of neuromuscular transmission and leading to muscle weakness that worsens with exertion.
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Chromosome location
CHRNB1 is located on chromosome 17 at band p13.1, a region near the short arm terminus. The gene spans genomic DNA on the minus strand and comprises multiple exons that encode the 501-amino-acid beta-1 subunit. Chromosome 17p13.1 contains several other genes involved in neuromuscular and neurological function, and structural variants affecting this region can have pleiotropic effects.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in CHRNB1 typically follow an autosomal recessive inheritance pattern, meaning that affected individuals carry biallelic variants (two altered copies, one inherited from each parent). Variants include missense changes that disrupt receptor assembly or gating, nonsense mutations that truncate the protein, and splice-site alterations that affect transcript processing. The specific functional consequence of a variant influences the severity and clinical presentation of associated myasthenic syndrome.
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.1218-9_1218-7del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 2A |
c.727C>T | p.Arg243Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 2C |
c.823G>T | p.Glu275Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 2A |
c.865G>A | p.Val289Met | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 2C |
c.883del | p.Ala295fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 2A |
GRCh38/hg38 17p13.1(chr17:7454200-7454618)x0 | - | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 2C |
c.1072_1073del | p.Leu358fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 2A |
c.1102_1103del | p.Asp368fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 2A |
c.270G>A | p.Trp90Ter | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 2A |
c.863del | p.Thr288fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 2A |
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
Biallelic pathogenic variants in CHRNB1 are associated with congenital myasthenic syndrome, a group of inherited neuromuscular disorders characterised by fatigable weakness of skeletal muscles. Symptoms often present in infancy or early childhood and may include feeding difficulties, delayed motor milestones, ptosis, and episodes of respiratory insufficiency. The severity can vary considerably depending on the residual function of the affected receptor complexes. Some individuals experience relatively mild weakness, while others have more significant impairment requiring ongoing medical management.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CHRNB1 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
CHRNB1 is included on multiple NHS Genomic Medicine Service gene panels with green (high evidence) ratings. It appears on the Congenital Myasthenic Syndrome panel (R80), the Arthrogryposis panel (R83), the Fetal Anomalies panel (R21), and the Developmental Disorders Genotype-to-Phenotype (DDG2P) database. These panel memberships reflect strong clinical evidence linking CHRNB1 variants to neuromuscular presentations and support its use in diagnostic genomic testing within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern is associated with CHRNB1-related conditions?
CHRNB1-related congenital myasthenic syndrome follows an autosomal recessive inheritance pattern, meaning an affected individual has inherited a pathogenic variant from each parent. Carriers with one variant typically do not show symptoms.
How does CHRNB1 contribute to muscle contraction?
The CHRNB1 protein is a structural component of the nicotinic acetylcholine receptor at the neuromuscular junction. When acetylcholine binds, the receptor opens an ion channel that depolarises the muscle membrane, triggering contraction.
Why is CHRNB1 included on NHS gene panels?
CHRNB1 is on NHS panels for congenital myasthenic syndrome, arthrogryposis, and foetal anomalies due to strong clinical evidence linking biallelic variants to neuromuscular weakness and developmental presentations.