In other species: domestic cat , horse , pig , taurine cattle , goat , sheep , water buffalo

Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 160800 (trait) , 255700 (trait) , 118425 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1999

Cross-species summary: Myotonia congenita

Species-specific description: Myotonia is a chloride channel disorder characterized by delayed skeletal muscle relaxation after contraction. Predominant signs include a stiff gait and skeletal muscle hypertrophy. Genetic tests are available for the miniature schnauzer and Australian cattle dog. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Inheritance: Although heterozygotes have heterodimeric chloride channels in their skeletal muscle, they appear clinically normal (Rhodes et al., 1999). Rodrigues et al. (2020) "The family history and pedigree analysis suggested an autosomal recessive inheritance pattern [in American Bulldogs]...."

Mapping: CFA16

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in himans, goats and mice), Rhodes et al. (1999) identified a causative variant [OMIAvariatnID:62]in the miniature schnauzer as a C to T substitution that changes the amino acid from threonine to methionine [p.T268M] in the CLCN1 gene, which encodes the skeletal muscle voltage-dependent chloride channel. By using the same functional candidate gene approach, Finnigan et al. (2007) identified a causative variant in an Australian cattle dog as a single base pair insertion (g2665insA) in the CLCN1 gene [omia.variant:609], "which would result in a frameshift with a stop codon 51 base pairs (bp) downstream. This mutation effectively truncates [CLCN1] after amino acid 888 (of 977)". Quitt et al. (2018): "Whole exome sequencing [of an affected Labrador Retriever puppy] revealed a case-specific homozygous variant in CLCN1, c.2275A > T resulting in a premature stop codon, p.R759X [omia.variant:1041]. The CLCN1 variant was absent from the genomes of 127 Labrador Retriever controls and 474 control dogs from other breeds." Rodrigues et al. (2020) investigated CLNC1 as a candidate gene in an American Bulldog with hereditary myotonia: "The molecular analysis revealed a frameshift mutation NM_001003124.2:c.436_437insCTCT that resulted in a frameshift and a premature stop codon NP_001003124.1:pTyr146SerfsTer49 [omia.variant:1364]. Two aberrant alternative CLCN1 transcripts were observed in an affected dog, the expected transcript with the 4 bp insertion, NM_001003124.2:r.436_437insctct, and an unexpected transcript containing parts of intron 6 in addition to the insertion in exon 4, NM_001003124.2:[r.436_437insctct;r.774_775ins79]." Chimenas et al. (2023) "describe ... a complex CLCN1 variant in a mixed-breed dog with clinical and electromyographic signs of HM. ... After sequencing the CLCN1 gene, a complex variant was found in exon 6 c.[705T>G; 708del; 712_732del; omia.variant:1570], resulting in a premature stop codon in exon 7 and a protein that was 717 amino acids shorter than the normal CLC protein. The myotonic dog was identified as homozygous recessive for the complex CLCN1 variant; its parents were heterozygous, and its male littermate was homozygous wild-type."
Shelton et al. (2024) investigated "two young French bulldogs with dysphagia and increased muscle mass in the shoulder and neck ... ." The authors conducted whole genome sequencing analysis and identified "a homozygous 8 bp duplication insertion variant in the CLCN1 gene [omia.variant:1678] resulting in a frameshift and premature stop codon (NP_001003124.1. p. F811Lfs*39) ... ."

Clinical features: Signs in miniature schnauzers include a stiff gait most pronounced at the onset of movement and during rapid changes in posture (turning quickly, falling), which may diminish with exercise. Other signs include severe skeletal muscle hypertrophy, difficulty rising, increased respiratory sounds, difficulty swallowing, and ptyalism beginning around 2 to 3 months of age. Associated superior prognathism may be a closely segregating trait (Gracis et al., 2000). Signs in the Australian cattle dog are similar, including skeletal muscle hypertrophy and generalized stiffness (Finnigan et al., 2007).
Two French bulldogs reported by Shelton et al. (2024) presented with muscle hypertrophy, swallowing disorders, and gait abnormalities.

Pathology: In affected dogs, skeletal muscle voltage-dependent chloride channels are unable to fully open at voltages near the resting membrane potential. There is a resultant delay in skeletal muscle relaxation after termination of the action potential, as depolarization is maintained longer than normal. Spontaneous triggering of action potentials independent of neuromuscular signaling induces frequent contraction and muscle hypertrophy (Rhodes et al., 1999).

Prevalence: Of 372 Miniature schnauzers tested from the US, Canada, Europe and Australia, 78.5% were normal, 20.4% were carriers, and 1.1% were affected. All affected dogs initially identified had a common ancestor (Bhalerao et al., 2002).

Control: Siblings of affected dogs and relatives of their parents should be tested. Breeding of affected dogs or carriers is discouraged.

Breeds: American Bulldog (Dog) (VBO_0200034), Australian Cattle Dog (Dog) (VBO_0200088), Border Collie (Dog) (VBO_0200193), Boxer (Dog) (VBO_0200210), Chow Chow (Dog) (VBO_0200361), Cocker Spaniel (Dog) (VBO_0200372), French Bulldog (Dog) (VBO_0201455), Great Dane (Dog) (VBO_0200623), Jack Russell Terrier (Dog) (VBO_0200724), Labrador Retriever (Dog) (VBO_0200800), Miniature Schnauzer (Dog) (VBO_0200896), Staffordshire Bull Terrier (Dog) (VBO_0201296).
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: