Abstract
ABSTRACTNemaline myopathy is a rare neuromuscular disorder that affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. 13 genes have been linked to nemaline myopathy (NM), all of which are associated with the thin filament of the muscle sarcomere. Of the 13 associated genes, mutations in NEBULIN (NEB) accounts for up to 50% of all cases. Currently, the disease is incompletely understood and there are no available therapeutics for patients. To address this urgent need for effective treatments for patients affected by NM, we conducted a large scale chemical screen in a zebrafish model of NEB-related NM and an N-ethyl-N-nitrosourea (ENU)-based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEB mutation in NM patients. Neither screen was able to identify a candidate for therapy development, highlighting the need to transition from conventional chemical therapeutics to gene-based therapies for the treatment of NM.
Highlights
Nemaline myopathy (NM) is a genetic muscle disorder characterized by severe muscle weakness and motor disabilities and defined by the pathognomonic appearance of nemaline rods on muscle biopsy (Darras, 2015; North and Ryan, 1993)
Patients affected by NM are classified into six groups based on their age of onset and the severity of motor and respiratory disability: severe congenital NM (16% of the NM population), intermediate congenital NM (20%), typical congenital NM (46%), childhood or juvenile onset NM (13%), adult onset NM (4%) and other forms (Ryan et al, 2001)
This concentration was determined based on previous zebrafish screens using this library, including our own work with a model of Duchenne muscular dystrophy (Waugh et al, 2014)
Summary
Nemaline myopathy (NM) is a genetic muscle disorder characterized by severe muscle weakness and motor disabilities and defined by the pathognomonic appearance of nemaline rods on muscle biopsy (Darras, 2015; North and Ryan, 1993). Patients affected by NM are classified into six groups based on their age of onset and the severity of motor and respiratory disability: severe congenital NM (16% of the NM population), intermediate congenital NM (20%), typical congenital NM (46%), childhood or juvenile onset NM (13%), adult onset NM (4%) and other forms (such as the autoimmune disease termed sporadic late onset NM) (Ryan et al, 2001). Mutations in at least 13 genes can cause NM (Gonorazky et al, 2018), with recessive mutations in NEBULIN (NEB) representing the most common overall cause. NEB encodes a large 600–900 kDa protein responsible for regulating thin filament length and actin-myosin cross bridge dynamics (Labeit et al, 2011). A few potential therapies, such as L-tyrosine and taurine, have been identified based
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