Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
01
02
2022
accepted:
25
07
2022
revised:
25
07
2022
pubmed:
11
8
2022
medline:
15
9
2022
entrez:
10
8
2022
Statut:
ppublish
Résumé
Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.
Identifiants
pubmed: 35948834
doi: 10.1007/s00401-022-02475-8
pii: 10.1007/s00401-022-02475-8
pmc: PMC9468088
doi:
Substances chimiques
Agrin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
707-731Informations de copyright
© 2022. The Author(s).
Références
Bauché S, Boerio D, Davoine C-S, Bernard V, Stum M, Bureau C et al (2013) Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome. Neuromuscul Disord NMD 23:998–1009. https://doi.org/10.1016/j.nmd.2013.07.005
doi: 10.1016/j.nmd.2013.07.005
pubmed: 24011702
Boillée S, Velde CV, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59. https://doi.org/10.1016/j.neuron.2006.09.018
doi: 10.1016/j.neuron.2006.09.018
pubmed: 17015226
Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392. https://doi.org/10.1126/science.1123511
doi: 10.1126/science.1123511
pubmed: 16741123
Bouchecareilh M, Marza E, Caruso M-E, Chevet E (2011) Small GTPase Signaling and the unfolded protein response. In: Methods in enzymology. Elsevier, pp 343–360
Brown RH, Al-Chalabi A (2017) Amyotrophic lateral sclerosis. N Engl J Med 377:162–172. https://doi.org/10.1056/NEJMra1603471
doi: 10.1056/NEJMra1603471
pubmed: 28700839
Cotman SL, Halfter W, Cole GJ (2000) Agrin binds to β-amyloid (aβ), accelerates aβ fibril formation, and is localized to aβ deposits in alzheimer’s disease brain. Mol Cell Neurosci 15:183–198. https://doi.org/10.1006/mcne.1999.0816
doi: 10.1006/mcne.1999.0816
pubmed: 10673326
Couteaux R, Taxi J (1952) Distribution of the cholinesterase activity at the level of the myoneural synapse. Comptes Rendus Hebd Seances Acad Sci 235:434–436
D’Amico D, Biondi O, Januel C, Bezier C, Sapaly D, Clerc Z et al (2022) Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway. Neuropathol Appl Neurobiol 48:e12816. https://doi.org/10.1111/nan.12816
doi: 10.1111/nan.12816
pubmed: 35338505
de Lamotte JD, Polentes J, Roussange F, Lesueur L, Feurgard P, Perrier A et al (2021) Optogenetically controlled human functional motor endplate for testing botulinum neurotoxins. Stem Cell Res Ther 12:599. https://doi.org/10.1186/s13287-021-02665-3
doi: 10.1186/s13287-021-02665-3
pubmed: 34865655
pmcid: 8647380
Doppler K, Hemprich A, Haarmann A, Brecht I, Franke M, Kröger S et al (2021) Autoantibodies to cortactin and agrin in sera of patients with myasthenia gravis. J Neuroimmunol 356:577588. https://doi.org/10.1016/j.jneuroim.2021.577588
doi: 10.1016/j.jneuroim.2021.577588
pubmed: 33962172
Edom F, Mouly V, Barbet JP, Fiszman MY, Butler-Browne GS (1994) Clones of human satellite cells can express in vitro both fast and slow myosin heavy chains. Dev Biol 164:219–229. https://doi.org/10.1006/dbio.1994.1193
doi: 10.1006/dbio.1994.1193
pubmed: 8026624
Eusebio A, Oliveri F, Barzaghi P, Ruegg MA (2003) Expression of mouse agrin in normal, denervated and dystrophic muscle. Neuromuscul Disord 13:408–415. https://doi.org/10.1016/S0960-8966(03)00036-1
doi: 10.1016/S0960-8966(03)00036-1
pubmed: 12798796
Finsterer J (2019) Congenital myasthenic syndromes. Orphanet J Rare Dis 14:57. https://doi.org/10.1186/s13023-019-1025-5
doi: 10.1186/s13023-019-1025-5
pubmed: 30808424
pmcid: 6390566
Gasperi C, Melms A, Schoser B, Zhang Y, Meltoranta J, Risson V et al (2014) Anti-agrin autoantibodies in myasthenia gravis. Neurology 82:1976–1983. https://doi.org/10.1212/WNL.0000000000000478
doi: 10.1212/WNL.0000000000000478
pubmed: 24793185
Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE et al (1996) Agrin acts via a MuSK receptor complex. Cell 85:513–523
doi: 10.1016/S0092-8674(00)81252-0
Hamburger V, Hamilton HL (1992) A series of normal stages in the development of the chick embryo. 1951. Dev Dyn Off Publ Am Assoc Anat 195:231–272. https://doi.org/10.1002/aja.1001950404
doi: 10.1002/aja.1001950404
Henderson, CE, Bloch-Gallego, E, Camu, W (2022) Purified embryonic motoneurons. In: Cohen J, Wilkin G (eds) London nerve cell culture: a practical approach. Oxford Univ. Press, pp 69–81
Huzé C, Bauché S, Richard P, Chevessier F, Goillot E, Gaudon K et al (2009) Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet 85:155–167. https://doi.org/10.1016/j.ajhg.2009.06.015
doi: 10.1016/j.ajhg.2009.06.015
pubmed: 19631309
pmcid: 2725239
Jacquier A, Bellouze S, Blanchard S, Bohl D, Haase G (2009) Astrocytic protection of spinal motor neurons but not cortical neurons against loss of Als2/alsin function. Hum Mol Genet 18:2127–2139. https://doi.org/10.1093/hmg/ddp136
doi: 10.1093/hmg/ddp136
pubmed: 19304783
Jacquier A, Buhler E, Schäfer MK, Bohl D, Blanchard S, Beclin C et al (2006) Alsin/Rac1 signaling controls survival and growth of spinal motoneurons. Ann Neurol 60(1):105–117. https://doi.org/10.1002/ana.20886
doi: 10.1002/ana.20886
pubmed: 16802292
Jacquier A, Delorme C, Belotti E, Juntas-Morales R, Solé G, Dubourg O et al (2017) Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. Acta Neuropathol Commun 5:55. https://doi.org/10.1186/s40478-017-0457-1
doi: 10.1186/s40478-017-0457-1
pubmed: 28709447
pmcid: 5513089
Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD (2009) TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284:20329–20339. https://doi.org/10.1074/jbc.M109.010264
doi: 10.1074/jbc.M109.010264
pubmed: 19465477
pmcid: 2740458
Karakaya M, Ceyhan-Birsoy O, Beggs AH, Topaloglu H (2017) A novel missense variant in the AGRN gene; congenital myasthenic syndrome presenting with head drop. J Clin Neuromuscul Dis 18:147–151. https://doi.org/10.1097/CND.0000000000000132
doi: 10.1097/CND.0000000000000132
pubmed: 28221305
pmcid: 5436270
Kim N, Stiegler AL, Cameron TO, Hallock PT, Gomez AM, Huang JH et al (2008) Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 135:334–342. https://doi.org/10.1016/j.cell.2008.10.002
doi: 10.1016/j.cell.2008.10.002
pubmed: 18848351
pmcid: 2933840
Lin S, Maj M, Bezakova G, Magyar JP, Brenner HR, Ruegg MA (2008) Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice. Proc Natl Acad Sci USA 105:11406–11411. https://doi.org/10.1073/pnas.0801683105
doi: 10.1073/pnas.0801683105
pubmed: 18685098
pmcid: 2497462
Liu I-H, Uversky VN, Munishkina LA, Fink AL, Halfter W, Cole GJ (2005) Agrin binds α-synuclein and modulates α-synuclein fibrillation. Glycobiology 15:1320–1331. https://doi.org/10.1093/glycob/cwj014
doi: 10.1093/glycob/cwj014
pubmed: 16037493
Maselli RA, Fernandez JM, Arredondo J, Navarro C, Ngo M, Beeson D et al (2012) LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet 131:1123–1135. https://doi.org/10.1007/s00439-011-1132-4
doi: 10.1007/s00439-011-1132-4
pubmed: 22205389
Matsuda T, Cepko CL (2004) Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci USA 101:16–22. https://doi.org/10.1073/pnas.2235688100
doi: 10.1073/pnas.2235688100
pubmed: 14603031
Maury Y, Côme J, Piskorowski RA, Salah-Mohellibi N, Chevaleyre V, Peschanski M et al (2015) Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat Biotechnol 33:89–96. https://doi.org/10.1038/nbt.3049
doi: 10.1038/nbt.3049
pubmed: 25383599
Mérien A, Tahraoui-Bories J, Cailleret M, Dupont J-B, Leteur C, Polentes J et al (2021) CRISPR gene editing in pluripotent stem cells reveals the function of MBNL proteins during human in vitro myogenesis. Hum Mol Genet 31:41–56. https://doi.org/10.1093/hmg/ddab218
doi: 10.1093/hmg/ddab218
pubmed: 34312665
pmcid: 8682758
Moll J, Barzaghi P, Lin S, Bezakova G, Lochmüller H, Engvall E et al (2001) An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 413:302–307. https://doi.org/10.1038/35095054
doi: 10.1038/35095054
pubmed: 11565031
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H et al (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622. https://doi.org/10.1038/nn1876
doi: 10.1038/nn1876
pubmed: 17435755
pmcid: 3799799
Nicole S, Chaouch A, Torbergsen T, Bauché S, de Bruyckere E, Fontenille M-J et al (2014) Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain J Neurol 137:2429–2443. https://doi.org/10.1093/brain/awu160
doi: 10.1093/brain/awu160
O’Connor E, Cairns G, Spendiff S, Burns D, Hettwer S, Mäder A et al (2019) Modulation of Agrin and RhoA pathways ameliorates movement defects and synapse morphology in MYO9A-depleted zebrafish. Cells 8:848. https://doi.org/10.3390/cells8080848
doi: 10.3390/cells8080848
pmcid: 6721702
Ohkawara B, Shen X, Selcen D, Nazim M, Bril V, Tarnopolsky MA et al (2020) Congenital myasthenic syndrome–associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner. JCI Insight. https://doi.org/10.1172/jci.insight.132023
doi: 10.1172/jci.insight.132023
pubmed: 32271162
pmcid: 7205260
Ohno K, Rahman MA, Nazim M, Nasrin F, Lin Y, Takeda J et al (2017) Splicing regulation and dysregulation of cholinergic genes expressed at the neuromuscular junction. J Neurochem 142:64–72. https://doi.org/10.1111/jnc.13954
doi: 10.1111/jnc.13954
pubmed: 28072465
Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci Off J Soc Neurosci 20:6048–6054
doi: 10.1523/JNEUROSCI.20-16-06048.2000
Pęziński M, Daszczuk P, Pradhan BS, Lochmüller H, Prószyński TJ (2020) An improved method for culturing myotubes on laminins for the robust clustering of postsynaptic machinery. Sci Rep 10:4524. https://doi.org/10.1038/s41598-020-61347-x
doi: 10.1038/s41598-020-61347-x
pubmed: 32161296
pmcid: 7066178
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. https://doi.org/10.1056/NEJMra0909142
doi: 10.1056/NEJMra0909142
pubmed: 20107219
Reddy UR, Venkatakrishnan G, Roy AK, Chen J, Hardy M, Mavilio F et al (1991) Characterization of two neuroblastoma cell lines expressing recombinant nerve growth factor receptors. J Neurochem 56:67–74
doi: 10.1111/j.1471-4159.1991.tb02563.x
Rodríguez Cruz PM, Palace J, Beeson D (2018) The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes. Int J Mol Sci 19:1677. https://doi.org/10.3390/ijms19061677
doi: 10.3390/ijms19061677
pmcid: 6032286
Rudell JB, Maselli RA, Yarov-Yarovoy V, Ferns MJ (2019) Pathogenic effects of agrin V1727F mutation are isoform specific and decrease its expression and affinity for HSPGs and LRP4. Hum Mol Genet 28:2648–2658. https://doi.org/10.1093/hmg/ddz081
doi: 10.1093/hmg/ddz081
pubmed: 30994901
pmcid: 6687949
Scaturro M, Posteraro P, Mastrogiacomo A, Zaccaria ML, De Luca N, Mazzanti C et al (2003) A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa. Biochem Biophys Res Commun 309:96–103
doi: 10.1016/S0006-291X(03)01533-X
Viotti C (2016) ER to golgi-dependent protein secretion: the conventional pathway. In: Pompa A, De Marchis F (eds) Unconventional protein secretion: methods and protocols. Springer, New York, pp 3–29
doi: 10.1007/978-1-4939-3804-9_1
Wang A, Xiao Y, Huang P, Liu L, Xiong J, Li J et al (2020) Novel NtA and LG1 mutations in agrin in a single patient causes congenital myasthenic syndrome. Front Neurol 11:239. https://doi.org/10.3389/fneur.2020.00239
doi: 10.3389/fneur.2020.00239
pubmed: 32328026
pmcid: 7160337
Wu H, Xiong WC, Mei L (2010) To build a synapse: signaling pathways in neuromuscular junction assembly. Dev Camb Engl 137:1017–1033. https://doi.org/10.1242/dev.038711
doi: 10.1242/dev.038711
Xi J, Yan C, Liu W-W, Qiao K, Lin J, Tian X et al (2017) Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome. Orphanet J Rare Dis. https://doi.org/10.1186/s13023-017-0732-z
doi: 10.1186/s13023-017-0732-z
pubmed: 29258548
pmcid: 5735900
Yoon S-B, Young-Ho P, Choi S-A, Yang H-J, Jeong P-S, Cha J-J et al (2019) Real-time PCR quantification of spliced X-box binding protein 1 (XBP1) using a universal primer method. PLoS ONE 14:e0219978. https://doi.org/10.1371/journal.pone.0219978
doi: 10.1371/journal.pone.0219978
pubmed: 31329612
pmcid: 6645673
Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L (2008) LRP4 serves as a coreceptor of agrin. Neuron 60:285–297. https://doi.org/10.1016/j.neuron.2008.10.006
doi: 10.1016/j.neuron.2008.10.006
pubmed: 18957220
pmcid: 2743173
Zhang Y, Dai Y, Han J-N, Chen Z-H, Ling L, Pu C-Q et al (2017) A novel AGRN mutation leads to congenital myasthenic syndrome only affecting limb-girdle muscle. Chin Med J (Engl) 130:2279–2282. https://doi.org/10.4103/0366-6999.215332
doi: 10.4103/0366-6999.215332