Congenital Myasthenic Syndromes (CMS), which are a heterogeneous group of inborn diseases characterized by impaired transmission of electrical impulses at the neuromuscular junction (NMJ), result from defects in one of multiple genes involved with the function of the NMJ. During the last century, defects in genes encoding the adult acetylcholine receptor (AChR) subunit genes (CHRNA1, CHRNB1, CHRND, CHRNE), and the acetylcholinesterase (AChE) collagenic tail (COLQ) were shown to cause several forms of CMS. During the last decade the genes encoding six other molecular targets, including the enzyme choline acetyltransferase (CHAT), rapsyn (RAPSN), the voltage-gated muscle sodium channel (SCN4A), the muscle-specific kinase (MUSK), Dok-7 (DOK7) and the fetal subunit of the AChR (CHRNG), have been demonstrated to be implicated in the pathogenesis of other types of CMS. We recently reported an additional target for mutations causing CMS, which is the gene encoding laminin beta 2 (LAMB2), bringing up the number of genes associated with CMS, to a total of twelve. Several other defective genes are likely to be involved in the pathogenesis of CMS since in a large number of patients affected with CMS no abnormalities can be found in the genes listed above. The proposed research is driven by the hypothesis that an inborn defect of any essential protein of the NMJ, for which no effective substituting molecule is available, can result in a CMS. However, a particularly challenging problem for detecting genetic defects causing CMS and preventing the reoccurrence of these diseases is the fact that there is a very large number of possible candidate genes and only very few clues in the CMS phenotype that can assist with the search for the causative mutation. In response to this challenge, the first specific aim of this project is to utilize conventional and novel methods of identification of the various types of CMS and their underlying genetic defects using clinical data;a special type of muscle biopsy, which includes intracellular microelectrode studies;electron microscopy of the NMJ and immunohistochemistry;as well as conventional and novel techniques for DNA analysis. The second specific aim of the project is to conduct expression studies in mammalian cell lines to characterize the effects of the discovered mutations. The long term goal of the project is to gain a better understating of the pathogenesis of CMS which may lead to effective forms of treatment for these neuromuscular disorders.

Public Health Relevance

This project will study a rare form of hereditary neuromuscular disorders, congenital myasthenic syndromes (CMS). Current understanding of these diseases is incomplete, and for many forms of CMS the underlying genetic defects are unknown. The proposed research will investigate the feasibility of applying novel techniques of identification of complex genetic defects causing CMS to determine the underlying cause and resulting effects of those forms of CNS for which no genetic association has been made, thereby bringing us closer to treatments for a large group of afflicted patients for whom there is currently no effective treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Stewart, Randall R
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University of California Davis
Schools of Medicine
United States
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Maselli, Ricardo A; Vázquez, Jessica; Schrumpf, Leah et al. (2018) Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A. Mol Genet Genomic Med 6:434-440
Maselli, Ricardo A; Arredondo, Juan; Vázquez, Jessica et al. (2018) A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5. Ann N Y Acad Sci 1413:119-125
Maselli, Ricardo A; Arredondo, Juan; Vázquez, Jessica et al. (2017) Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission. Am J Med Genet A 173:2240-2245
Arredondo, Juan; Lara, Marian; Gospe Jr, Sídney M et al. (2015) Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations. Hum Mutat 36:881-93
Arredondo, Juan; Lara, Marian; Ng, Fiona et al. (2014) COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina. Hum Genet 133:599-616
Maselli, R A; Arredondo, J; Nguyen, J et al. (2014) Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clin Genet 85:166-71
Richman, David P; Nishi, Kayoko; Morell, Stuart W et al. (2012) Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes. Arch Neurol 69:453-60
Maselli, Ricardo A; Fernandez, Jose M; Arredondo, Juan et al. (2012) LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet 131:1123-35
Richman, David P; Yu, Yawei; Lee, Ting-Ting et al. (2012) Dominantly inherited myotonia congenita resulting from a mutation that increases open probability of the muscle chloride channel CLC-1. Neuromolecular Med 14:328-37
Maselli, R A; Arredondo, J; Cagney, O et al. (2011) Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clin Genet 80:444-51

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