OMIA 000698-9615 : Myotonia in Canis lupus familiaris

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

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 160800 (trait) , 255700 (trait) , 118425 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1999

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 mutation 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 mutation in an Australian cattle dog as a single base pair insertion (g2665insA) in the CLCN1 gene, "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. 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 . 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]."

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).

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.

Genetic testing: There is a test available to detect the mutation in the miniature schnauzer (Bhalerao et al., 2002) and the Australian cattle dog (Finnigan et al., 2007).

Breeds: American Bulldog, Australian Cattle Dog, Border Collie, Boxer, Chow Chow, Great Dane, Jack Russell Terrier, Labrador Retriever, Miniature Schnauzer, Staffordshire Bull Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CLCN1 chloride channel, voltage-sensitive 1 Canis lupus familiaris 16 NC_051820.1 (6227304..6196701) CLCN1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
609 Australian Cattle Dog Border Collie Myotonia CLCN1 insertion, small (<=20) Naturally occurring variant CanFam3.1 16 g.6344748_6344749insT c.2647_2648insA p.(R883Qfs*18) NM_001003124.2; NP_001003124.1; published as c.2665insA; p.(R889fs); coordinates in the table have been updated to a recent reference genome and / or transcript 2007 17552451
1041 Labrador Retriever Myotonia CLCN1 nonsense (stop-gain) Naturally occurring variant CanFam3.1 16 g.6348929T>A c.2275A>T p.(R759X) Quitt et al. (2018): "Chr16:6348929 T A CLCN1 ENSCAFG00000003619.3 stopgain" 2018 29934119
62 Miniature Schnauzer Myotonia CLCN1 missense Naturally occurring variant CanFam3.1 16 g.6366383G>A c.803C>T p.(T268M) 1999 10452529 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
1364 American Bulldog Myotonia CLCN1 insertion, small (<=20) Naturally occurring variant CanFam3.1 16 g.6369245_6369246insAGAG c.436_437insCTCT p.(Y146Sfs*49) cDNA and protein position based on NM_001003124.2 and NP_001003124.1 2020 33246886

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2021 Cerda-Gonzalez, S., Packer, R.A., Garosi, L., Lowrie, M., Mandigers, P.J.J., O'Brien, D.P., Volk, H.A. :
International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification. J Vet Intern Med 35:1218-1230, 2021. Pubmed reference: 33769611. DOI: 10.1111/jvim.16108.
2020 Rodrigues, D.J., Damasceno, A.D., Araújo, C.E.T., Torelli, S.R., Fonseca, L.G.H., Delfiol, D.J.Z., Oliveira-Filho, J.P., Araújo-Júnior, J.P., Borges, A.S. :
Hereditary myotonia in American Bulldog associated with a novel frameshift mutation in the CLCN1 gene. Neuromuscul Disord 30:991-998, 2020. Pubmed reference: 33246886. DOI: 10.1016/j.nmd.2020.10.007.
2018 Quitt, P.R., Hytönen, M.K., Matiasek, K., Rosati, M., Fischer, A., Lohi, H. :
Myotonia congenita in a Labrador Retriever with truncated CLCN1. Neuromuscul Disord 28:597-605, 2018. Pubmed reference: 29934119. DOI: 10.1016/j.nmd.2018.05.002.
2016 Donner, J., Kaukonen, M., Anderson, H., Möller, F., Kyöstilä, K., Sankari, S., Hytönen, M., Giger, U., Lohi, H. :
Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. PLoS One 11:e0161005, 2016. Pubmed reference: 27525650. DOI: 10.1371/journal.pone.0161005.
2013 Broeckx, B.J., Coopman, F., Verhoeven, G.E., Van Haeringen, W., van de Goor, L., Bosmans, T., Gielen, I., Saunders, J.H., Soetaert, S.S., Van Bree, H., Van Neste, C., Van Nieuwerburgh, F., Van Ryssen, B., Verelst, E., Van Steendam, K., Deforce, D. :
The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. PLoS One 8:e74811, 2013. Pubmed reference: 24069350. DOI: 10.1371/journal.pone.0074811.
2009 Lobetti, RG. :
Myotonia congenita in a Jack Russell terrier. J S Afr Vet Assoc 80:106-7, 2009. Pubmed reference: 19831273.
2007 Finnigan, DF., Hanna, WJ., Poma, R., Bendall, AJ. :
A novel mutation of the CLCN1 gene associated with myotonia hereditaria in an Australian cattle dog. J Vet Intern Med 21:458-63, 2007. Pubmed reference: 17552451.
2003 Bhalerao, D.R., Rajpurochit, Y., Vite, C.H., Giger, U. :
Detection of a genetic mutation for myotonia congenita among Miniature Schnauzers and identification of a common carrier ancestor (vol 63, pg 1443, 2002) American Journal of Veterinary Research 64:25, 2003.
2002 Bhalerao, D.R., Rajpurohit, Y., Vite, C.H., Giger, U. :
Detection of a genetic mutation for myotonia congenita among Miniature Schnauzers and identification of a common carrier ancestor American Journal of Veterinary Research 63:1443-1447, 2002. Pubmed reference: 12371774.
2000 Gracis, M., Keith, D., Vite, C.H. :
Dental and craniofacial findings in eight miniature schnauzer dogs affected by myotonia congenita: preliminary results. J Vet Dent 17:119-27, 2000. Pubmed reference: 11968937.
1999 Rhodes, T.H., Vite, C.H., Giger, U., Patterson, D.F., Fahlke, C., George, A.L. :
A missense mutation in canine ClC-1 causes recessive myotonia congenita in the dog FEBS Letters 456:54-58, 1999. Pubmed reference: 10452529.
Vite, C.H., Melniczek, J., Patterson, D., Giger, U. :
Congenital myotonic myopathy in the miniature schnauzer: An autosomal recessive trait Journal of Heredity 90:578-580, 1999. Pubmed reference: 10544501.
1998 Smith, B.F., Braund, K.G., Steiss, J.E., Simpson, S.T., Cox, N.R., Sorjonen, D.C. :
Possible adult onset myotonic dystrophy in a boxer Journal of Veterinary Internal Medicine 12:120, 1998. Pubmed reference: 9560770.
Swinney, G.B., Foster, S.F., Church, D.B., Malik, R. :
Myotonia associated with hyperadrenocorticism in two dogs Australian Veterinary Journal 76:722-724, 1998. Pubmed reference: 9862060.
Vite, C.H., Cozzi, F., Rich, M., Klide, A.K., Volk, S.W., Lombardo, R. :
Myotonic myopathy in a miniature Schnauzer: case report and data suggesting abnormal chloride conductance across the muscle membrane. J Vet Intern Med 12:394-7, 1998. Pubmed reference: 9773418.
1995 Hill, S.L., Shelton, G.D., Lenehan, T.M. :
Myotonia in a cocker spaniel Journal of the American Animal Hospital Association 31:506-509, 1995. Pubmed reference: 8581546.
1991 Poncelet, L., Fontaine, J., Balligand, M. :
Myotonia in two aged poodles. Vet Rec 128:599, 1991. Pubmed reference: 1897093.
1989 Kortz, G. :
Canine myotonia. Semin Vet Med Surg (Small Anim) 4:141-5, 1989. Pubmed reference: 2682887.
1987 McKerrell, R.E. :
Myotonia in man and animals: confusing comparisons. Equine Vet J 19:266-7, 1987. Pubmed reference: 3622451.
1986 Honhold, N., Smith, D.A. :
Myotonia in the great dane. Vet Rec 119:162, 1986. Pubmed reference: 3776062. DOI: 10.1136/vr.119.7.162-a.
Shores, A., Redding, R.W., Braund, K.G., Simpson, S.T. :
Myotonia congenita in a Chow Chow pup. J Am Vet Med Assoc 188:532-3, 1986. Pubmed reference: 3957761.
1985 Amann, J.F., Tomlinson, J., Hankison, J.K. :
Myotonia in a chow chow. J Am Vet Med Assoc 187:415-7, 1985. Pubmed reference: 4030477.
1983 Shires, P.K., Nafe, L.A., Hulse, D.A. :
Myotonia in a Staffordshire terrier. J Am Vet Med Assoc 183:229-32, 1983. Pubmed reference: 6885599.
1974 Wentink, G.H., Hartman, W., Koeman, J.P. :
Three cases of myotonia in a family of Chows Tijdschrift voor Diergeneeskunde 99:729-731, 1974. Pubmed reference: 4536400.

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