Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery

Abstract

Mutations in muscle ACh receptors cause slow-channel syndrome (SCS) and Escobar syndrome, two forms of congenital myasthenia. SCS is a dominant disorder with mutations reported for all receptor subunits except γ. Escobar syndrome is distinct, with mutations located exclusively in γ, and characterized by developmental improvement of muscle function. The zebrafish mutant line, twister , models SCS in terms of a dominant mutation in the α subunit (α twi ) but shows the behavioral improvement associated with Escobar syndrome. Here, we present a unique electrophysiological study into developmental improvement for a myasthenic syndrome. The embryonic α twi βδγ receptor isoform produces slowly decaying synaptic currents typical of SCS that transit to a much faster decay upon the appearance of adult ε, despite the α twi mutation. Thus, the continued expression of α twi into adulthood is tolerated because of the ε expression and associated recovery, raising the likelihood of unappreciated myasthenic cases that benefit from the γ−ε switch.

Zebrafish mutants of the neuromuscular junction: swimming in the gene pool

“…The zebrafish mutants discussed in this review provided valuable insights into the pathophysiology of some neurological disorders. Sofa potato and twitch once had mutations in genes later identified to cause human diseases [ 13 , 24 , 25 , 40 ], and physiological study of twister indicated unappreciated benefits of subunit switch in myasthenic cases [ 9 ].…”

“…AChRs at NMJs comprise of five subunits (thus called pentamers): two α1 s, one β1, one δ, and one ε or γ, with the ε and γ subunits being interchangeable. The γ subunit is expressed early in development and, in mammals and fish, is replaced by the ε subunit as the animal matures [ 8 , 9 ]. A notable exception to this long-held view, which will be discussed in detail below [ 10 , 11 ] (Fig.…”

“…Interestingly this phenotype can only be observed during early development [ 19 ], and heterozygotes recover from their behavioral defect as they age, which coincides with a change of synaptic current kinetics. This recovery is based on the developmental subunit switch from λ to ε [ 9 ].

Fig.

…”

Synaptic silencing of fast muscle is compensated by rewired innervation of slow muscle

“…Nicotinic AChRs are pentamers composed of 21s, 1, , and  (or ) subunits, which are all specific to skeletal muscles (13). In zebrafish as well as in mammals,  subunits are expressed in larvae and change to  as the animal matures (14,15). Recent studies showed that AChRs in slow muscles of zebrafish lack / subunits and are composed of only , , and  subunits (13).…”

Sequence Variations inpxr (nr1i2)From Zebrafish (Danio rerio) Strains Affect Nuclear Receptor Function

“…Zebrafish (Danio rerio) is a model organism that is widely used in genetics, developmental biology, medicine, pharmacology, and toxicology (reviewed in [Alestrom et al, 2006;Carvan et al, 2007;Dai et al, 2014;Kamstra et al, 2014;Lieschke and Currie, 2007;Quaife et al, 2012;Stegeman et al, 2010;Walogorsky et al, 2012]). Its widespread use is due in part to a well-studied and annotated genome, rapid development, short life cycle, and ease of genetic manipulation.…”