Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies
| العنوان: | Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies |
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| المؤلفون: | Matt Parton, Wei Wei Liu, Maryam Sedghi, Andrew M. Schaefer, Maria Elena Farrugia, Katsiaryna Belaya, Susan Maxwell, Jacqueline Palace, Hanns Lochmüller, Simon J. McGowan, Keivan Basiri, Anna Sarkozy, Wyatt W. Yue, Kate Bushby, Matthew Pitt, David Beeson, Richard E. Petty, Timothy J. Walls, Pedro M. Rodríguez Cruz, Marta Bertoli, Robin Kennett, Francesco Muntoni |
| المصدر: | Brain |
| بيانات النشر: | Oxford University Press, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Adult, Male, Pathology, medicine.medical_specialty, Weakness, glycosylation, Adolescent, DNA Mutational Analysis, Neuromuscular transmission, Neuromuscular Junction, GMPPB, Transfection, Neuromuscular junction, dystroglycan, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, Humans, Repetitive nerve stimulation, Muscular dystrophy, Myopathy, Dystroglycans, Muscle, Skeletal, 030304 developmental biology, Family Health, Myasthenic Syndromes, Congenital, 0303 health sciences, business.industry, neurotransmission defect, DPAGT1, Original Articles, Congenital myasthenic syndrome, medicine.disease, Magnetic Resonance Imaging, Nucleotidyltransferases, 3. Good health, medicine.anatomical_structure, HEK293 Cells, congenital myasthenic syndrome, Immunology, Mutation, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery |
| الوصف: | Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication. 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. |
| اللغة: | English |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4caad57ca8c6d0ca5b81ac994de9e2ceTest http://europepmc.org/articles/PMC4547052Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4caad57ca8c6d0ca5b81ac994de9e2ce |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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