A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers

Area of Science:

• Genetics
• Neuroscience
• Veterinary Medicine

Background:

• Congenital myasthenic syndromes (CMSs) are rare genetic neuromuscular junction disorders causing early-onset fatigable weakness.
• Mutations in proteins of the neuromuscular junction, particularly nicotinic acetylcholine receptor (AChR) subunits, are implicated in CMS.
• CMS was first identified in Jack Russell Terriers (JRTs) as an autosomal recessive condition with junctional AChR deficiency.

Purpose of the Study:

• To characterize the genetic basis of CMS in contemporary JRT cases.
• To identify the specific genetic mutation responsible for CMS in JRTs.
• To confirm the long-standing presence of this mutation in the JRT breed.

Main Methods:

• Clinical and electromyographic evaluation of JRT littermates with suspected CMS.
• Immunochemical analysis to quantify AChR protein content.
• Microsatellite marker analysis to identify candidate genes (CHRNB1, CHRNE) for CMS.
• Exonic and splice site sequencing of CHRNE to pinpoint the causative mutation.

Main Results:

• Confirmed ~90% reduction in AChR protein content in affected JRTs.
• Identified a single base insertion in exon 7 of the CHRNE gene.
• The mutation predicts a frameshift and premature stop codon, leading to non-functional AChR.
• The same pathogenic CHRNE mutation was found in archival JRT tissues from 34 years prior.

Conclusions:

• A specific frameshift mutation in the CHRNE gene is the cause of CMS in Jack Russell Terriers.
• This genetic defect leads to a severe deficiency of functional nicotinic acetylcholine receptors at the neuromuscular junction.
• The mutation has been present in the JRT breed for at least 34 years, indicating a long-standing genetic issue.