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DOK7
docking protein 7
The DOK7 gene provides instructions for a protein crucial in forming and maintaining connections between nerve cells and muscle cells, known as the neuromuscular junction. The DOK7 gene encodes a protein called docking protein 7, which is essential for the proper development and function of the neuromuscular junction.
DOK7 is located on the short (p) arm of chromosome 4, at band 4p16.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DOK7 gene produces docking protein 7, which plays a critical role in establishing and maintaining the neuromuscular junction. This junction serves as the interface where nerve cells transmit signals to muscle cells, a process fundamental for all voluntary muscle activity. The DOK7 protein assists in organising key structures at this junction, ensuring efficient nerve-to-muscle communication.
When the DOK7 protein does not function correctly, often due to inherited genetic alterations, muscle function can be impaired. These conditions typically present as muscle weakness, with variability in severity and age of onset.
What the gene does
The DOK7 gene is responsible for creating the docking protein 7, which contributes to the construction of the neuromuscular junction. This protein's primary function is to activate another protein called MuSK. Research indicates that once DOK7 switches on MuSK, this activated enzyme helps organise proteins important for developing and maintaining the neuromuscular junction. MuSK is involved in gathering the acetylcholine receptor on the surface of muscle cells at this junction. These receptors are critical for signalling between nerve and muscle cells, ultimately triggering muscle contraction.
By supporting the proper arrangement of acetylcholine receptors, DOK7 enables effective communication from nerves to muscles. This signalling mechanism is essential for coordinated voluntary muscle activity. When DOK7 does not work properly, this pathway can be disrupted, potentially leading to muscle weakness.
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Chromosome location
The DOK7 gene is situated on the short arm of chromosome 4, specifically at position 4p16.3. This genomic location specifies where the gene resides within the human genome.
Protein structure
The DOK7 protein consists of 504 amino acids and features several distinct domains and regions. It includes a Pleckstrin homology domain spanning amino acids 4-109. An IRS-type phosphotyrosine-binding domain is located between amino acids 105-210. Additionally, the protein contains multiple intrinsically disordered regions, specifically from amino acids 210-229, 249-351, and 411-483.
Key variants
Variants within the DOK7 gene can alter the protein's structure or function, leading to impaired neuromuscular junction development or maintenance. These genetic changes can affect how effectively the DOK7 protein activates downstream signalling pathways essential for muscle function. The clinical impact of DOK7 variants depends on the specific change and its effect on protein activity.
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.1001_1011dup | p.Ser338fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 3 |
c.1236C>A | p.Cys412Ter | Pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.1243_1340del | p.Pro415fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.1247_1250dup | p.Asp417fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.1324_1357del | p.Cys442fs | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 10 |
c.1339_1342del | p.Leu447fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 3 |
c.1378C>T | p.Gln460Ter | Pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.1378del | p.Gln460fs | Pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.1395_1453del | p.Leu466fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 10 |
c.473G>A | p.Arg158Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
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 DOK7 gene are primarily associated with a group of inherited disorders known as congenital myasthenic syndromes. These conditions are characterised by muscle weakness and easy fatigability that typically begins shortly after birth. In rare instances, DOK7 variants have also been linked to foetal akinesia deformation sequence, a severe condition involving a lack of movement before birth and multiple physical abnormalities.
- Congenital myasthenic syndrome (DOK7)
- Congenital myasthenic syndromes Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic DOK7 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 DOK7 gene is included in several NHS Genomic Medicine Service national test panels, indicating its clinical relevance in the UK. It is assessed within panels for conditions such as Arthrogryposis (R83), Congenital myaesthenic syndrome (R80), Congenital myopathy (R81), Foetal anomalies (R21), and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82). This inclusion highlights the importance of DOK7 testing for diagnosing and managing individuals with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
There is currently no specific lifestyle advice known to prevent or directly manage conditions caused by DOK7 gene variants. General healthy lifestyle recommendations, such as balanced nutrition and appropriate physical activity, may support overall well-being but do not alter the genetic basis of these conditions. Always consult a healthcare professional for personalised advice.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific supplements can prevent, treat, or mitigate the effects of conditions caused by DOK7 gene variants. Individuals considering any supplements should first discuss this with a healthcare provider, as some supplements may interact with medications or have other health implications.
Frequently asked questions
What is the role of the DOK7 gene?
The DOK7 gene provides instructions for making the DOK7 protein, which is essential for establishing and maintaining the neuromuscular junction. This junction is where nerves connect with muscles to transmit signals, enabling muscle movement.
What conditions are associated with DOK7 gene variants?
Variants in the DOK7 gene are mainly associated with congenital myasthenic syndromes, a group of inherited disorders causing muscle weakness. In rare cases, they can also be linked to foetal akinesia deformation sequence.
How is congenital myasthenic syndrome inherited?
Congenital myasthenic syndrome caused by DOK7 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
- Engel AG. Current status of the congenital myasthenic syndromes. Neuromuscular disorders : NMD. 2012. PMID: 22104196
- Engel AG, Shen XM, Selcen D. What have we learned from the congenital myasthenic syndromes. Journal of molecular neuroscience : MN. 2010. PMID: 19688192
- 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
- Selcen D, Milone M, Shen XM. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Annals of neurology. 2008. PMID: 18626973
- Kinali M, Beeson D, Pitt MC. Congenital myasthenic syndromes in childhood: diagnostic and management challenges. Journal of neuroimmunology. 2008. PMID: 18707767
- Müller JS, Herczegfalvi A, Vilchez JJ. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain : a journal of neurology. 2007. PMID: 17439981