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Dok-7/MuSK signaling and a congenital myasthenic syndrome.

ABSTRACT: Skeletal muscle contraction is controlled by motor neurons, which contact the muscle at the neuromuscular junction (NMJ). The formation and maintenance of the NMJ, which includes the aggregation of densely packed clusters of acetylcholine receptor (AChR) opposite the motor nerve terminal, is orchestrated by muscle-specific receptor tyrosine kinase, MuSK. Recently, a MuSK-interacting cytoplasmic adaptor-like protein Dok-7 was identified and its localization at the postsynaptic region of the NMJ was revealed. Mice lacking Dok-7 have a phenotype indistinguishable from MuSK-deficient mice, and fail to form both AChR clusters and NMJs. In cultured myotubes, Dok-7 is required for MuSK activation and AChR clustering. Thus, Dok-7 is essential for neuromuscular synaptogenesis and it appears that the regulatory interaction of Dok-7 with MuSK is integrally involved in this process. In humans there are both autoimmune and genetic causes of defective neuromuscular transmission that gives rise to the fatigable muscle weakness known as myasthenia. DOK7 has been found to be a major locus for mutations that underlie a genetic form of myasthenia with a characteristic 'limb girdle' pattern of muscle weakness (DOK7 CMS). Patients with DOK7 CMS have small, simplified NMJs but normal AChR function. The most common mutation causes a COOH-terminal truncation, which greatly impairs Dok-7's ability to activate MuSK. Recently, a series of differing DOK7 mutations have been identified, which affect not only the COOH-terminal region but also the NH2-terminal moiety. The study of these mutations may help understand the underlying pathogenic mechanism of DOK7 CMS.

SUBMITTER: Yamanashi Y

PROVIDER: S-EPMC2859609 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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Dok-7/MuSK signaling and a congenital myasthenic syndrome.

Yamanashi Y Y Higuch O O Beeson D D

Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 20080701

Skeletal muscle contraction is controlled by motor neurons, which contact the muscle at the neuromuscular junction (NMJ). The formation and maintenance of the NMJ, which includes the aggregation of densely packed clusters of acetylcholine receptor (AChR) opposite the motor nerve terminal, is orchestrated by muscle-specific receptor tyrosine kinase, MuSK. Recently, a MuSK-interacting cytoplasmic adaptor-like protein Dok-7 was identified and its localization at the postsynaptic region of the NMJ w ...[more]

PMID: 19108574

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Project description:Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Dataset Information

Dok-7/MuSK signaling and a congenital myasthenic syndrome.

Publications

Dok-7/MuSK signaling and a congenital myasthenic syndrome.

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