LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin

Ricardo A Maselli, Jose M. Fernandez, Juan Arredondo, Carmen Navarro, Maian Ngo, David Beeson, Órla Cagney, D. Colette Williams, Robert L. Wollmann, Vladimir Yarov-Yarovoy, Michael J Ferns

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Abstract

We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by >100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to α-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to α-dystroglycan, mimics non-neural (z-) agrin and are important determinants of the pathogenesis of the disease.

Original languageEnglish (US)
Pages (from-to)1123-1135
Number of pages13
JournalHuman Genetics
Volume131
Issue number7
DOIs
StatePublished - Jul 2012

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Congenital Myasthenic Syndromes
Agrin
Mutation
Dystroglycans
Neuromuscular Junction
Cholinergic Receptors
Nonsense Codon
Presynaptic Terminals
Laminin
Missense Mutation
Acetylcholinesterase
Muscle Cells
Cluster Analysis
Cytoplasm
Phosphorylation
Biopsy
Muscles

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. / Maselli, Ricardo A; Fernandez, Jose M.; Arredondo, Juan; Navarro, Carmen; Ngo, Maian; Beeson, David; Cagney, Órla; Williams, D. Colette; Wollmann, Robert L.; Yarov-Yarovoy, Vladimir; Ferns, Michael J.

In: Human Genetics, Vol. 131, No. 7, 07.2012, p. 1123-1135.

Research output: Contribution to journalArticle

Maselli, Ricardo A ; Fernandez, Jose M. ; Arredondo, Juan ; Navarro, Carmen ; Ngo, Maian ; Beeson, David ; Cagney, Órla ; Williams, D. Colette ; Wollmann, Robert L. ; Yarov-Yarovoy, Vladimir ; Ferns, Michael J. / LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. In: Human Genetics. 2012 ; Vol. 131, No. 7. pp. 1123-1135.
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T1 - LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin

AU - Maselli, Ricardo A

AU - Fernandez, Jose M.

AU - Arredondo, Juan

AU - Navarro, Carmen

AU - Ngo, Maian

AU - Beeson, David

AU - Cagney, Órla

AU - Williams, D. Colette

AU - Wollmann, Robert L.

AU - Yarov-Yarovoy, Vladimir

AU - Ferns, Michael J

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N2 - We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by >100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to α-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to α-dystroglycan, mimics non-neural (z-) agrin and are important determinants of the pathogenesis of the disease.

AB - We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by >100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to α-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to α-dystroglycan, mimics non-neural (z-) agrin and are important determinants of the pathogenesis of the disease.

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