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DOK7
docking protein 7
The DOK7 gene encodes a protein vital for the proper formation and maintenance of the neuromuscular junction, the connection point between nerve and muscle cells. The DOK7 gene provides instructions for a protein called docking protein 7, which plays a key role in the signalling necessary for muscle movement.
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, or docking protein 7, is integral to the development and function of the neuromuscular junction. This specialised synapse is where nerve impulses are transmitted to muscle fibres, enabling muscle contraction and movement. The DOK7 protein facilitates this critical communication, and its proper function is essential for motor control and overall muscle health.
Variations within the DOK7 gene can disrupt this process, leading to conditions primarily characterised by muscle weakness and easy fatigability.
What the gene does
The DOK7 gene provides instructions for a protein involved in establishing and maintaining the neuromuscular junction. This crucial area facilitates the transmission of signals from nerve cells to muscle cells, which is necessary for muscle contraction. The DOK7 protein achieves this by activating another protein called MuSK (Muscle-specific Kinase).
MuSK, once activated by DOK7, helps to organise various proteins at the neuromuscular junction, particularly the acetylcholine receptor (AChR). The AChR is critical for receiving nerve signals on the muscle cell surface, thereby ensuring efficient signal transmission and proper muscle function. Therefore, DOK7 plays an essential role in coordinating the molecular machinery required for effective nerve-to-muscle communication.
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Chromosome location
The DOK7 gene is situated on the short (p) arm of chromosome 4 at position 16.3, specifically located at 4p16.3. This region of the human genome contains instructions vital for various biological processes, including the development and function of the neuromuscular system.
Protein structure
The DOK7 protein comprises 504 amino acids and features several distinct functional regions. It includes a PH (Pleckstrin Homology) domain spanning amino acids 4-109, which is typically involved in binding to phospholipids and targeting proteins to membranes. An IRS-type PTB (Phosphotyrosine Binding) domain is located between amino acids 105-210, often mediating interactions with phosphorylated tyrosine residues on other proteins. Additionally, the protein contains multiple disordered regions: one from amino acids 210-229, another from 249-351, and a third from 411-483. These intrinsically disordered regions often play roles in protein-protein interactions and signalling.
Key variants
Variants within the DOK7 gene can alter the structure or function of the docking protein 7. These genetic changes can impair the protein's ability to facilitate proper neuromuscular junction development and maintenance. The clinical impact of DOK7 variants can range in severity, leading to a spectrum of associated conditions.
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.1361_1374del | p.Leu454fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 10 |
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 |
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
Variants in the DOK7 gene are primarily associated with Congenital myasthenic syndrome (DOK7), which is a specific type of Congenital myasthenic syndromes. These are a group of inherited conditions characterised by muscle weakness and fatigue that typically begin in infancy or early childhood. In rare instances, DOK7 variants have also been linked to foetal akinesia deformation sequence, a severe condition marked by reduced foetal 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 currently recognised within the NHS Genomic Medicine Service, being featured on several green R-panels. These include Arthrogryposis (R83), Congenital myaesthenic syndrome (R80), Congenital myopathy (R81), Foetal anomalies (R21), and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82). Its presence on these panels indicates its established role in the diagnosis and understanding of these conditions within a clinical setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the DOK7 gene?
The DOK7 gene provides instructions for a protein that is essential for forming and maintaining the neuromuscular junction, which is the critical connection point between nerve cells and muscle cells for signal transmission and muscle movement.
What conditions are associated with DOK7 gene variants?
Variants in the DOK7 gene are primarily associated with congenital myasthenic syndromes, a group of inherited disorders characterised by muscle weakness and fatigue. In rare cases, they have also been linked to foetal akinesia deformation sequence.
How is the DOK7 gene involved in muscle movement?
The DOK7 protein activates another protein called MuSK, which helps organise crucial components, such as acetylcholine receptors, at the neuromuscular junction. This organisation ensures that nerve signals are efficiently transmitted to muscle cells, enabling proper muscle contraction.
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