In other species: taurine cattle , indicine cattle (zebu)

Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 605809 (trait) , 616324 (trait) , 608931 (trait) , 100725 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Jack Russel terrier type congenital myasthenic syndrome; post-synaptic congenital myasthenic syndrome; myasthenia gravis-like disease

Molecular basis: By sequencing two positional functional candidate genes, Rinz et al. (2015) concluded that a likely causal mutation in Jack Russell Terriers is "a single base insertion [omia.variant:614, published as c.633_634insC] in exon 7 of CHRNE that predicts a frameshift mutation and a premature stop codon [p.Gly212Argfs*274]". Herder et al. (2017) investigated a litter of Heideterriers, in which 4 out of 11 puppies showed pronounced muscle weakness. Only one of these puppies was available for genetic analysis. Herder et al. (2017) performed whole genome sequencing and identified a homozygous single nucleotide insertion into the coding sequence of the CHRNE gene (omia.variant:804; XM_014113502.1:c.1436_1437insG). The insertion was predicted to lead to a frameshift and premature stop codon (XP_013968977.1:p.Ser479ArgfsTer14). This variant was absent from the genomes of 274 control dogs. Based on the earlier findings in Jack Russell Terriers and other species, Herder et al. (2017) concluded that "it is plausible that the CHRNE variant may have caused a myasthenia gravis-like disease in the investigated puppy."
Peterson et al. (2024) investigated 2 English Springer Spaniels and their unaffected dam and a Smooth Fox Terrier with congenital myasthenic syndrome. The authors seequenced exons 3–13 of the CHRNE candidate gene and discovered a missense mutation in the English Springer Spaniels (omia.variant:1729; published as chr5:31915101C>A; XP_013968977.2:p.(S503R)) and a 1-bp insertion in the Smooth Fox Terrier that was previously reported in Heideterrier (omia.variant:804) as likely causal variants.

Clinical features: Rinz et al. (2015) reported that affected Jack Russell Terrier (JRT) pups appeared normal until 6 weeks of age. "Affected JRT pups showed generalized muscle weakness at 7 weeks of age, walking only briefly for 10–15 short-strided steps before sitting or lying down." Treatment with anticholinesterase drug resulted in temporary improvement of muscle weakness. "Development of drug resistance necessitated euthanasia." Herder et al. (2017): "In a litter of Heideterriers, four out of 11 puppies showed a lack of reflexes and coordination of the front limbs 6 days after birth. Consciousness and general condition of these animals was reported to be normal, and none showed fever. The four affected puppies displayed weakness progressing over the course of the day and peaking at night time. The most severely affected animal showed falling to the side and recumbency, while still being alert and trying to play in this position."

Pathology: Rinz et al. (2015): "No indication of a primary nervous system or muscle disorder was found on post-mortem examination [of affected Jack Russell Terriers]. Occasional groups of atrophic myofibers of both fiber types were noted in cryosections stained with the myofibrillar ATPase reaction. Several end-plates were identified by the esterase reaction product staining, but no AChRs were detectable in serial cryosections by labeling with fluorescent α-bungarotoxin." Herder et al. (2017) reported lack of significant pathological findings in most muscles except for mild lipomatosis musculorum in the M. triceps in a Heideterrier.

Breeds: English Springer Spaniel (Dog) (VBO_0200497), Heideterrier (Dog) (VBO_0200666), Jack Russell Terrier (Dog) (VBO_0200724), Smooth Fox Terrier (Dog) (VBO_0201258).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: