Congenital myasthenic syndrome due to a TOR1AIP1 mutation: a new disease pathway for impaired synaptic transmission

Brain Communications
Judith CossinsDavid Beeson

Abstract

Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked end-plate potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum...Continue Reading

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Citations

Jun 25, 2021·Neuropathology and Applied Neurobiology·Edoardo MalfattiGianina Ravenscroft

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Methods Mentioned

BETA
glycosylation
biopsy
exome sequencing
biopsies
protein assay
chip
Assay
transmission electron microscopy
RNA-seq
transgenic

Software Mentioned

UCSC genome Browser
Graphpad Prism
rpkm
ANNOVAR
Novoalign
ImageJ
Ensembl

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