OMIA:001374-9615 : Centronuclear myopathy, HACD1-related in Canis lupus familiaris |
Categories: Muscle phene
Possibly relevant human trait(s) and/or gene(s) (MIM number): 610467 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant 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_051806.1 (19652419..19672996) | HACD1 | Homologene, Ensembl , NCBI gene |
Variants
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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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 924 | Labrador | Centronuclear myopathy, HACD1-related | HACD1 | insertion, gross (>20) | Naturally occurring variant | CanFam3.1 | 2 | g.19371988_19371989ins[N[236];CACACAAAGGTTT] | c.203_204ins[N[236];CACACAAAGGTTT] | NM_001025269.1; published as insertion of a 236 bp antisense canine tRNA-like SINE (EMBL accession no. AJ876906), flanked on both sides by a 13 bp direct duplication of the insertion site; resulting in multiple splicing defects | 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 . |
Edit History
- Created by Frank Nicholas on 26 Oct 2010
- Changed by Frank Nicholas on 12 Dec 2011
- Changed by Frank Nicholas on 22 Oct 2012
- Changed by Frank Nicholas on 13 May 2013
- Changed by Frank Nicholas on 12 Dec 2017