OMIA 001374-9615 : Myopathy, centronuclear in Canis lupus familiaris

See the equivalent entry at NCBI

Possible human homologue (MIM number): 610467

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key mutation known: yes

Year key mutation first reported: 2005

Cross-species summary: Centronuclear Myopathy (CNM)

Species-specific name: Type II fiber deficiency; Autosomal recessive muscular dystrophy; Hereditary myopathy of Labrador retrievers (HMLR)

History: The first clinical description of this disorder was by Kramer et al. (1976).

Inheritance: Tiret et al. (2003) showed that this disorder is autosomal recessive.

Mapping: Conducting a genome scan with 66 microsatellites on a four-generation pedigree that "comprised 40 dogs among which 20 were affected (12 females and 8 males)" Tiret et al. (2003) mapped this disorder to the centromeric region of chromosome CFA2. Subsequent fine mapping reduced this to an "18.1-cM interval between markers FH2087U and AHT132". Subsequent FISH-mapping "established orthology between the centromeric region of CFA2 and the GDI2-cREM human segment (HSA10p15/HSA10p12.1-p11.1)".

Molecular basis: Pelé et al. (2005) determined the molecular basis of this disorder by adopting a comparative positional cloning approach. Having mapped the canine disorder as described in the Mapping section above, they then studied the 208 human genes that are located in the orthologous region of chromosome HSA10p. Based on tissue expression and sequence motif, the most likely of these 208 genes was PTPLA (protein tyrosine phosphatase-like, member A). Sequencing of the canine PTPLA gene revealed the causative mutation as an insertion of a "tRNA-derived short interspersed repeat element (SINE)" in exon 2 ("PTPLA*g9459-9460ins236") which "has a striking effect on the maturation of PTPLA mRNA, whereby it can be spliced out, partially exonized or involved in multiple exon-skipping. As a result, the amount of wild-type transcripts falls to 1% in affected muscles."

PTPLA is known as HACD1 in NCBI Gene.

Prevalence: Maurer et al. (2012) conducted a comprehensive world-wide survey by genotyping 7,426 Labradors from 18 countries for the PTPLA mutant reported by Pelé et al. (2005). All 80 affected dogs from 8 countries were homozygous for the same mutant allele, and none of the 1.172 heterozygous dogs from 13 countries was affected. The highest % of carriers were "found in the UK (19%), the USA (13%) and Canada (11,5%)". The UK estimate is similar to the UK estimate of 22%, reported by Owczarek-Lipska et al. (2011). Maurer et al. (2012) concluded that the mutant allele "resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires".

Breed: Labrador Retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
HACD1 protein tyrosine phosphatase-like (proline instead of catalytic arginine), member A Canis lupus familiaris 2 NC_006584.3 (19362488..19383090) HACD1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Labrador Myopathy, centronuclear HACD1 insertion, gross (>20) g.9459-9460ins236 2005 15829503

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.
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.
2012 Maurer, M., Mary, J., Guillaud, L., Fender, M., Pelé, M., Bilzer, T., Olby, N., Penderis, J., Shelton, G.D., Panthier, J.J., Thibaud, J.L., Barthélémy, I., Aubin-Houzelstein, G., Blot, S., Hitte, C., Tiret, L. :
Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide. PLoS One 7:e46408, 2012. Pubmed reference: 23071563. DOI: 10.1371/journal.pone.0046408.
2011 Gentilini, F., Zambon, E., Gandini, G., Rosati, M., Spadari, A., Romagnoli, N., Turba, M.E., Gernone, F. :
Frequency of the allelic variant of the PTPLA gene responsible for centronuclear myopathy in Labrador Retriever dogs as assessed in Italy. J Vet Diagn Invest 23:124-6, 2011. Pubmed reference: 21217042.
Owczarek-Lipska, M., Thomas, A., André, C., Hölzer, S., Leeb, T. :
[Frequency of gene defects in selected European retriever populations]. Schweiz Arch Tierheilkd 153:418-20, 2011. Pubmed reference: 21866517. DOI: 10.1024/0036-7281/a000236.
2005 Pelé, M., Tiret, L., Kessler, J.L., Blot, S., Panthier, J.J. :
SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum Mol Genet 14:1417-27, 2005. Pubmed reference: 15829503. DOI: 10.1093/hmg/ddi151.
2003 Tiret, L., Blot, S., Kessler, J.L., Gaillot, H., Breen, M., Panthier, J.J. :
The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome 2 Human Genetics 113:297-306, 2003. Pubmed reference: 12884002. DOI: 10.1007/s00439-003-0984-7.
2002 Bley, T., Gaillard, C., Bilzer, T., Braund, K.G., Faissler, D., Steffen, F., Cizinauskas, S., Neumann, J., Vogtli, T., Equey, R., Jaggy, A. :
Genetic aspects of labrador retriever myopathy Research in Veterinary Science 73:231-236, 2002. Pubmed reference: 12443679.
Blot, S., Tiret, L., Devillaire, A.C., Fardeau, M., Dreyfus, P.A. :
Phenotypic description of a canine centronuclear myopathy. Journal of Neurological Science 199:S9, 2002.
2001 Olby, N.J., Sharp, N.J., Anderson, L.V., Kunkel, L.M., Bönnemann, C.G. :
Evaluation of the dystrophin-glycoprotein complex, alpha-actinin, dysferlin and calpain 3 in an autosomal recessive muscular dystrophy in Labrador retrievers. Neuromuscul Disord 11:41-9, 2001. Pubmed reference: 11166165.
1996 Gortel, K., Houston, D.M., Kuiken, T., Fries, C.L., Boisvert, B. :
Inherited myopathy in a litter of Labrador retrievers. Can Vet J 37:108-10, 1996. Pubmed reference: 8640649.
1988 Amann, JF., Laughlin, MH., Korthuis, RJ. :
Muscle hemodynamics in hereditary myopathy of Labrador retrievers. Am J Vet Res 49:1127-30, 1988. Pubmed reference: 2458692.
Watson, A.D., Farrow, B.R., Middleton, D.J., Smyth, J.B. :
Myopathy in a Labrador retriever. Aust Vet J 65:226-7, 1988. Pubmed reference: 3421890.
1987 McKerrell, R.E., Braund, K.G. :
Hereditary myopathy in Labrador Retrievers: clinical variations. Journal of Small Animal Practice 28:479–489, 1987.
Moore, MP., Reed, SM., Hegreberg, GA., Kramer, JW., Alexander, JE., Meyer, KM., Bryan, GM. :
Electromyographic evaluation of adult Labrador retrievers with type-II muscle fiber deficiency. Am J Vet Res 48:1332-6, 1987. Pubmed reference: 3662204.
1986 McKerrell, RE., Braund, KG. :
Hereditary myopathy in Labrador retrievers: a morphologic study. Vet Pathol 23:411-7, 1986. Pubmed reference: 3750734.
1984 McKerrell, R.E., Anderson, J.R., Herrtage, M.E., Littlewood, J.D., Palmer, A.C. :
Generalised muscle weakness in the Labrador retriever. Vet Rec 115:276, 1984. Pubmed reference: 6495580.
1976 Kramer, J.W., Hegreberg, G.A., Bryan, G.M., Myers, K.M., Ott, R.L. :
A muscle disorder of Labrador Retrievers characterized by deficiency of type II muscle fibers Journal of the American Veterinary Medical Association 169:817-820, 1976. Pubmed reference: 977449.

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  • Created by Frank Nicholas on 26 Oct 2010
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 22 Oct 2012
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  • Changed by Frank Nicholas on 12 Dec 2017