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RAPSN
receptor associated protein of the synapse
The RAPSN gene provides instructions for making a protein essential for the proper formation and function of the neuromuscular junction, the connection point between nerves and muscles. The RAPSN gene is crucial for the production of the rapsyn protein, which plays a vital role in anchoring acetylcholine receptors at the neuromuscular junction.
RAPSN is located on the short (p) arm of chromosome 11, at band 11p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The RAPSN gene, also known as receptor associated protein of the synapse, is fundamental for healthy muscle function. It encodes a protein called rapsyn, which is critical for relaying signals between nerve cells and muscle cells.
Disruptions in the RAPSN gene can lead to disorders that affect muscle control and movement, particularly congenital myasthenic syndromes. RAPSN plays a key role in diagnosing and managing these conditions.
What the gene does
The RAPSN gene provides instructions for synthesising the rapsyn protein. This protein is essential for the neuromuscular junction, which is the specialised synapse where nerve impulses are transmitted to muscle fibres, triggering muscle contraction. Rapsyn's primary role is to bind to various subunits of the acetylcholine receptor (AChR) protein, located within the muscle cell membrane [PMID:10629007].
By binding to the AChR subunits, rapsyn helps to assemble and stabilise these receptors, ensuring they are correctly positioned and clustered at the neuromuscular junction. This clustering is vital for efficient signal transmission, allowing the neurotransmitter acetylcholine to effectively communicate with the muscle cell and initiate movement. Without functional rapsyn, the proper organisation of AChRs is compromised, leading to impaired nerve-muscle communication [PMID:10629007]. Research has shown that rapsyn's interaction with the AChR is critical for maintaining synaptic integrity and efficient signal transduction [PMID:10629007].
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Chromosome location
The RAPSN gene is located on chromosome 11, specifically at position 11p11.2. This chromosomal band refers to the short (p) arm of chromosome 11, within region 1, band 1, and sub-band 2. The gene spans approximately 412 amino acids in its protein product.
Protein structure
The rapsyn protein, encoded by the RAPSN gene, consists of several distinct domains critical for its function. It features a series of seven Tetratricopeptide Repeat (TPR) domains: TPR 1 (amino acids 6-39), TPR 2 (amino acids 83-116), TPR 3 (amino acids 123-156), TPR 4 (amino acids 163-196), TPR 5 (amino acids 206-239), TPR 6 (amino acids 246-279), and TPR 7 (amino acids 286-319). These TPR domains typically mediate protein-protein interactions, acting as scaffolds for multi-protein complexes. Additionally, the protein contains a RING-type (Zinc finger) domain located at amino acids 363-403, which is often involved in ubiquitination and other protein modification processes, contributing to rapsyn's regulatory role.
Key variants
Variants in the RAPSN gene can alter the structure or function of the rapsyn protein, impacting its ability to correctly assemble and anchor acetylcholine receptors at the neuromuscular junction. These genetic changes can range from single nucleotide changes to larger deletions or insertions within the gene sequence. Identifying specific variants is important for understanding their potential clinical implications and for genetic counselling.
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.1166+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.192+2T>G | - | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.210del | p.Ile70fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome |
c.288del | p.Cys97fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 11 |
c.3G>T | p.Met1Ile | Pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.531+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome |
c.733C>T | p.Gln245Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 2 |
c.966+1_966+2delinsAG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 2 |
c.990_993del | p.His329_Cys330insTer | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 11 |
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 RAPSN gene are associated with a group of inherited disorders known as congenital myasthenic syndromes. Specifically, this includes Congenital myasthenic syndrome (RAPSN). These conditions are characterised by impaired signal transmission at the neuromuscular junction, leading to muscle weakness and fatigue that can vary in severity. The symptoms typically begin in infancy or childhood and can affect muscles involved in eye movement, facial expression, speech, swallowing, and breathing. Another related condition is Multiple Pterygium Syndrome, which also has associations with RAPSN variants.
- Congenital myasthenic syndrome (RAPSN)
- Congenital myasthenic syndromes Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic RAPSN 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 RAPSN gene is included in several NHS England national genomic testing panels, indicating its recognised clinical significance within the UK healthcare system. It is part of the Arthrogryposis panel (R83), the Congenital myaesthenic syndrome panel (R80), the DDG2P panel, and the Foetal anomalies panel (R21). These inclusions highlight its role in a range of inherited conditions requiring genomic investigation.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the RAPSN gene?
The RAPSN gene provides instructions for making the rapsyn protein, which is crucial for assembling and anchoring acetylcholine receptors at the neuromuscular junction. This ensures effective communication between nerves and muscles.
What conditions are associated with RAPSN gene variants?
Variants in the RAPSN gene are primarily associated with congenital myasthenic syndromes, which are inherited disorders that cause muscle weakness due to impaired signal transmission at the neuromuscular junction. Multiple Pterygium Syndrome is also linked to RAPSN.
How is the RAPSN gene relevant to UK healthcare?
In the UK, the RAPSN gene is included in several NHS national genomic testing panels, such as those for Arthrogryposis, Congenital myaesthenic syndrome, DDG2P, and Foetal anomalies, reflecting its importance in diagnosing inherited conditions.
References
- Engel AG. Congenital myasthenic syndromes in 2012. Current neurology and neuroscience reports. 2012. PMID: 21997714
- Engel AG. Current status of the congenital myasthenic syndromes. Neuromuscular disorders : NMD. 2012. PMID: 22104196
- Barišić N, Chaouch A, Müller JS. Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2011. PMID: 21498094
- Milone M, Shen XM, Selcen D. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. Neurology. 2009. PMID: 19620612
- Beeson D, Webster R, Cossins J. Congenital myasthenic syndromes and the formation of the neuromuscular junction. Annals of the New York Academy of Sciences. 2008. PMID: 18567858
- Kinali M, Beeson D, Pitt MC. Congenital myasthenic syndromes in childhood: diagnostic and management challenges. Journal of neuroimmunology. 2008. PMID: 18707767