DOK7 – Congenital Myasthenic Syndrome 10

DOK7 encodes a cytoplasmic adaptor essential for MuSK activation at the neuromuscular junction and is causally associated with autosomal recessive Congenital Myasthenic Syndrome 10, characterized by fatigable proximal muscle weakness and a limb-girdle distribution (PMID:17452375).

Biallelic DOK7 variants have been identified in over 60 unrelated probands from more than 24 kinships, with a spectrum of loss-of-function alleles predominantly affecting exon 7, notably c.1124_1127dup (p.Pro504SerfsTer15) (PMID:17452375; PMID:22661499). Additional case series include 15 pediatric patients treated effectively with albuterol (PMID:26552645) and an adult-onset presentation during pregnancy responsive to fluoxetine and salbutamol (PMID:29395672).

Genetic studies reveal autosomal recessive inheritance with homozygous and compound heterozygous frameshift, splice-site, and missense mutations. Segregation across multiple families confirms cosegregation of biallelic alleles with disease, supporting high genetic evidence (affected relatives: 24).

Functional assays demonstrate that the common frameshift c.1124_1127dup (p.Pro504SerfsTer15) and over ten missense variants abrogate acetylcholine receptor clustering in patient‐derived cells. Zebrafish dok7 knockdown recapitulates neuromuscular junction synaptopathy with reduced AChR cluster size and aberrant slow muscle fiber integrity, consistent with loss‐of‐function pathogenesis (PMID:20147321; PMID:22661499).

No studies have disputed the DOK7–CMS10 association. Collectively, genetic and experimental data establish DOK7 haploinsufficiency as the mechanistic basis of CMS10, and also provide a robust framework for functional confirmation of novel variants.

Key Take-home: Biallelic DOK7 variants definitively cause autosomal recessive CMS10; genetic testing is recommended for early‐onset or atypical myasthenic presentations, and functional assays plus zebrafish models offer confirmatory evidence guiding diagnosis and potential therapy with β2‐adrenergic agonists.

References

• Brain • 2007 • Clinical features of the DOK7 neuromuscular junction synaptopathy. PMID:17452375
• 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 • 2012 • The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. PMID:22661499
• Pediatric neurology • 2016 • Effective Treatment With Albuterol in DOK7 Congenital Myasthenic Syndrome in Children. PMID:26552645
• Neuromuscular disorders : NMD • 2018 • DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine. PMID:29395672

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