DOK7 – Congenital Myasthenic Syndrome

DOK7 encodes a cytoplasmic adaptor protein essential for MuSK activation and acetylcholine receptor (AChR) clustering at the neuromuscular junction. Biallelic pathogenic variants in DOK7 underlie an autosomal recessive form of congenital myasthenic syndrome (CMS) characterized by a limb-girdle pattern of muscle weakness, fatigability, and variable facial and respiratory involvement.

Genetic evidence for DOK7-CMS includes identification of LoF and missense variants in at least 80 probands. Six unrelated patients were first described with the recurrent c.1124_1127dup (p.Pro504SerfsTer15) and c.1263dup (p.Ser422LeufsTer?) alleles (PMID:18161030). Subsequent series reported pathogenic variants in 27 patients from 24 kinships, all harboring at least one frameshift in exon 7 (PMID:17452375).

Segregation data demonstrate consistent autosomal recessive inheritance with multi-family confirmation: over 40 independent kinships have shown co-segregation of biallelic DOK7 variants with CMS phenotype (PMID:17452375; PMID:22661499).

The DOK7 variant spectrum comprises mainly frameshift and splice-site mutations leading to C-terminal truncation, as well as missense changes in the PH and PTB domains. A representative pathogenic allele is c.1124_1127dup (p.Pro504SerfsTer15), which abolishes MuSK binding.

Functional studies confirm that Dok7 deficiency disrupts early AChR cluster formation in zebrafish embryos, causing motility defects and simplified synapses (PMID:20147321). In patient-derived iPSCs, the intronic c.653-1G>C and p.Gly64Arg alleles impair Dok7 expression, reduce MuSK phosphorylation, and compromise AChR clustering in myotubes (PMID:36579833).

Clinically, patients do not benefit from anticholinesterase inhibitors and may worsen; however, adrenergic agonists such as ephedrine or salbutamol produce marked and sustained improvement in muscle strength and function.

Overall, the DOK7–CMS association is classified as Definitive based on extensive multi-family genetic data, strong segregation, and concordant functional assays. Key takeaway: genetic testing for DOK7 should be prioritized in limb-girdle CMS, as accurate diagnosis enables targeted adrenergic therapy and greatly improves outcomes.

References

• Brain • 2007 • Clinical features of the DOK7 neuromuscular junction synaptopathy. PMID:17452375
• Human Molecular Genetics • 2012 • The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. PMID:22661499
• Human Molecular Genetics • 2010 • Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes. PMID:20147321
• Human Molecular Genetics • 2023 • A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells. PMID:36579833
• Muscle & Nerve • 2008 • Variable phenotypes associated with mutations in DOK7. PMID:18161030

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