In other species: dog , domestic cat , 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)

Links to relevant human diseases in MONDO:

• MONDO:0009710: Thomsen and Becker disease

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Myotonia congenita

Species-specific description: As summarised by Valberg (2014), "Myotonic muscle disorders share the feature of delayed relaxation of muscle after mechanical stimulation or voluntary contraction due to abnormal muscle membrane conduction. Horses have three known forms of myotonia: myotonia congenita, myotonia dystrophica, and hyperkalemic periodic paralysis (HyPP)". This OMIA entry deals with Myotonia congentia. (FN thanks Izabela De Assis Rocha, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 15 April 2020)

Molecular basis: A gene defect in CLCN1 was then known to cause similar phenotypes in humans (see OMIM links above) and in goats (OMIA 000698-9925 and in dogs (OMIA 000698-9615), which led Wijnberg et al (2012) to adopt a comparative candidate gene approach. By sequencing "all exons and several introns of the equine CLCN1 gene [in] . . . DNA samples from the affected foal, its dam, its sire . . . and one unrelated control horse", and testing variants for consistency with autosomal recessive transmission of the disorder, Wijnberg et al. (2014) identified a likely causal variant as a single nucleotide polymorphism at c.1775A>C position (Genbank acc. XM_001915636). The c.1775A>C transversion led to the replacement of an aspartic acid by alanine in codon 592 (Genbank acc. XP_001915671) in the C-terminal cytoplasmatic domain of the skeletal muscle chloride channel 1 protein. This amino acid residue was found to be conserved in seven other species; therefore the described amino acid substitution has a potential impact on the formation of the functional ion channel (Wijnberg et al., 2012). (FN thanks Izabela De Assis Rocha, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 15 April 2020)

Clinical features: From the case report described in a New Forest Pony by Wijnberg et al. (2012), the main clinical signs of myotonia congenita are the "recurrent episodes of recumbency and difficulty to rise due to muscle stiffness". Occasionally, when the horse is stimulated, it "seemed hyperreactive and temporary protrusion of the third eyelid occurred due to retraction of the eye uni- or bilaterally". It is important to note that this case report included only one affected foal. (FN thanks Izabela De Assis Rocha, who provided the basis of this contribution, working under the supervision of Professor Ernie Bailey; 15 April 2020)

Prevalence: The occurrence of this variant in a wider sample of 42 additional New Forest ponies and 56 horses from 13 other breeds was consistent with it being causal of an autosomal recessive disorder in the New Forest breed: from the total 102 horses included in this study, Wijnberg et al (2012) found that the affected foal was the only homozygous C/C for the mutated allele 1775C, whereas its sire, its dam and seven other mares related to the foal were heterozygous A/C. All other horses here homozygous A/A for the wildtype allele 1775A.

Breed: New Forest Pony (Horse) (VBO_0001026).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: