CHRNA1
protein-codingcholinergic receptor nicotinic alpha 1 subunit, the group of Cholinergic receptors nicotinic subunits
Gene summary
The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]
- CHRNA
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~40.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009668
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011088
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012156
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009668
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012156
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012156
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011088
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012156
Submitter: ClinGen
CHRNA1 Related Congenital Myasthenic Syndrome is a clinically variable syndrome resulting from functional abnormalities of the postsynaptic neuromuscular junction. The CHRNA1 gene encodes the alpha subunit of the muscle nicotinic acetylcholine receptor (nAChR), a membrane spanning protein channel that controls signaling between nerve and muscle cells. Both autosomal recessive and autosomal dominant patterns of inheritance are observed. The autosomal recessive disease is due to absence or severely reduced protein expression which in turn reduces the number of nACh receptors, or functional alterations that limit channel opening time. The autosomal dominant disease is the result of prolonged opening and activity of the channel. The autosomal dominant disease is curated separately. Clinical features of autosomal recessive disease vary from mild to severe. Null variants or missense variants that result in severely reduced expression cause more severe features often with prenatal onset that can include fetal akinesia deformation sequence with joint contractures and pterygia, growth restriction, polyhydramnios, and fetal hydrops. Neonates have profound hypotonia and respiratory distress, requiring respiratory support and gavage feeding. Those with residual protein or variants that reduce channel opening time have a broader range of clinical symptoms that include muscle weakness, increased fatigability, facial diplegia, weakess of the ocular muscles, and ptosis. We have curated 16 variants in CHRNA1 (missense, nonsense, frameshift, splice variants, deletion) across 8 publications (PMIDs: 36092864, 33756069, 24121633, 18806275, 18252226, 12588888, 10195214, 22728938). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. The gene-disease association is also supported by experimental evidence showing reduced CHRNA1 expression and activity in patient cells, reduced CHRNA1 activity in NEK cells transfected with specific CHRNA1 variants, animal models including homozygous null variants which are lethal in mice and two separate zebrafish models (PMIDs: 18252226, 9475746, 34077687, 18806275, 24121633, 12588888). In summary, the CHRNA1 gene is definitively associated with autosomal recessive CHRNA1 Related Congenital Myasthenic Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date May 15, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0009668
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: Musculoskeletal; Neurologic; Pharmacogenomic
Rationale: Most individuals with CMS benefit from AChE inhibitors and/or potassium channel blocker 3,4-diaminopyridine (3,4-DAP), though caution must be used in giving 3,4-DAP to young children and individuals with fast-channel syndromes; For Slow-channel congenital myasthenic syndrome, effective treatment has been reported with therapies such as quinidine, fluoxetine, and ephedrine, while cholinesterase inhibitors and amifampridine should be avoided; Additional neurologic monitoring in pregnancy may be beneficial
Comments: Manifestations have been reported in heterozygotes
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CHRNA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000079.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 8 | 116 | 1 | 126 | |
| missense | 9 | 14 | 247 | 12 | 1 | 283 |
| nonsense | 8 | 4 | 1 | 13 | ||
| start loss | 2 | 2 | ||||
| frameshift | 6 | 9 | 1 | 16 | ||
| splice donor/acceptor (+/-2bp) | 1 | 7 | 8 | |||
| Total | 24 | 37 | 257 | 128 | 2 | 448 |
Highest pathogenic variant AF is 0.00003779547
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000070.1 | 9 | MANE Select | |
| Ensembl | ENSP00000261008.5 | 9 | MANE Select | |
| RefSeq | NP_001034612.1 | 10 | Standard | |
| Ensembl | ENSP00000261007.5 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| chrna1 | Danio rerio | Structure: Rohon-Beard neuron Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Effects of Botulinum toxin
- Neuronal System
- actions of nitric oxide in the heart
- agrin in postsynaptic differentiation
Biological Process
- skeletal muscle contraction
- cation transport
- signal transduction
- chemical synaptic transmission
- synaptic transmission, cholinergic
Molecular Function
- ion channel activity
- extracellular ligand-gated ion channel activity
- acetylcholine receptor activity
- acetylcholine-gated cation-selective channel activity
- acetylcholine binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- acetylcholine-gated channel complex
- cell surface
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261007
- Coding exons
- 10
- Length
- 16881
- Individuals with no LoFs
- 125690
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 58
- Defined
- 125748
- p
- 0.000231
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.722 | 250 | 284 | 0.880 | 0.0000175 | 3181 |
| Missense (PolyPhen) | 85 | 109.75 | 0.77448 | 1235 | ||
| Synonymous | -0.0812 | 113 | 112 | 1.01 | 0.00000775 | 939 |
| Loss of Function | 1.28 | 15 | 21.4 | 0.701 | 9.20e-7 | 251 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00069 | 0.00065 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00029 | 0.00028 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. {ECO:0000269|PubMed:27375219}.;
- Disease
- DISEASE: Note=The alpha subunit is the main focus for antibody binding in myasthenia gravis. Myasthenia gravis is characterized by sporadic muscular fatigability and weakness, occurring chiefly in muscles innervated by cranial nerves, and characteristically improved by cholinesterase-inhibiting drugs.; DISEASE: Myasthenic syndrome, congenital, 1A, slow-channel (CMS1A) [MIM:601462]: A common congenital myasthenic syndrome. Congenital myasthenic syndromes are characterized by muscle weakness affecting the axial and limb muscles (with hypotonia in early- onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1A is a slow-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in prolonged AChR channel opening episodes, prolonged endplate currents, and depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. {ECO:0000269|PubMed:16685696, ECO:0000269|PubMed:7619526, ECO:0000269|PubMed:8872460, ECO:0000269|PubMed:9158151, ECO:0000269|PubMed:9221765}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 1B, fast-channel (CMS1B) [MIM:608930]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS1B is a fast-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in brief opening and activity of the channel, with a rapid decay in endplate current, failure to achieve threshold depolarization of the endplate and consequent failure to fire an action potential. {ECO:0000269|PubMed:10195214, ECO:0000269|PubMed:12588888, ECO:0000269|PubMed:15079006}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.381
Intolerance Scores
- LoFtool
- 0.163
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.734
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |