X-Linked Myotubular Myopathy (XLMTM) in Labrador Retrievers
X-linked myotubular myopathy in Labrador Retrievers is an inherited muscle disease that manifests with generalized muscle weakness and progressive muscle atrophy in puppies.
Phenotype: This disorder is characterized by early onset (as early as 7 weeks of age) of signs that include generalized muscle weakness, progressive muscle atrophy, a hoarse bark, episodic collapse, droopy jaw, and difficulty eating. Without the option of intensive supportive care, and because this disease is progressive, affected puppies invariably require euthanasia between 3 and 6 months of age.
Mode of Inheritance:X-linked recessive
Alleles: N = Normal, MTML = X-linked myotubular myopathy
Breeds appropriate for testing: Labrador Retriever
Explanation of Results:
Males only have one X chromosome whereas females have two, therefore possible genotypes will differ by sex.
Female dogs with N/N genoytpe and male dogs with N genotype will not have X-linked myotubular myopathy, and cannot transmit this variant to their offspring.
Female dogs with N/MTML genotype will not have X-linked myotubular myopathy, but are carriers. If a carrier female is bred to a normal (N) male, all female puppies will be normal but 50% of them will be carriers. Among male puppies from this type of cross, 50% will be normal and 50% will be affected by X-linked myotubular myopathy.
Female dogs with MTML/MTML genotype and male dogs with MTML genotype will develop X-linked myotubular myopathy, a progressive muscle disease.
X-linked myotubular myopathy (XLMTM) is a subtype of centronuclear myopathies, rare genetic muscle disorders named after the central location of the muscle fiber nuclei. This disorder is characterized by early onset (as early as 7 weeks of age) of signs that include generalized muscle weakness, progressive muscle atrophy, a hoarse bark, episodic collapse, droopy jaw, and difficulty eating. Without the option of intensive supportive care, and because this disease is progressive, affected puppies invariably require euthanasia between 3 and 6 months of age.
XLMTM in Labrador Retrievers is caused by a single nucleotide change (c.465C>A) in exon 7 of the Myotubular Myopathy 1 (MTM1)gene located on the X chromosome. This mutation causes altered localization and reduced quantities of the myotubularin protein in affected dogs, leading to an excessive variability in muscle fiber size and the presence of central nuclei (as opposed to peripheral nuclei in normal dogs). According to published information (see reference below), the mutation is thought to have appeared recently and to have a restricted geographic localization in some pedigrees in Canada. Screening of a random set of Labradors Retrievers at the VGL determined that the MTM1 disease allele is rare in this breed, with frequency less than 1%.
The mode of inheritance for this disease is X-linked recessive. Females have two X chromosomes, therefore for a female to be affected she must have two copies of the defective MTM1 gene to develop XLMTM. Clinical signs are predominantly absent in females with one normal and one affected copy of the gene (carriers). Males, on the other hand, only have one X chromosome and therefore if they inherit the defective copy of the MTM1 gene they will develop XLMTM. If the inherited copy is normal, males will not have the disease.
Testing for XLMTM assists veterinarians with diagnosis of MTM1 and helps breeders identify carrier females to avoid matings that can produce affected dogs. When a carrier female is bred to a normal male, all female puppies will be normal but 50% of them will be carriers. Among male puppies, they always inherit their X chromosome from the dam so from this type of cross, 50% will be normal (those that inherit the X chromosome with the N version of MTM1) and 50% will be affected (those that inherit the X chromosome with the altered version of MTM1).
No copies of the MTM1 mutation detected. Female is normal.
1 copy of the MTM1 mutation detected. Female is a carrier and unaffected. If bred to an N male, 50% of female offspring are expected to be carriers and 50% of male offspring are expected to be affected.
2 copies of the MTM1 mutation detected. Female is affected. She has or will develop XLMTM.
No copy of the MTM1 mutation detected. Male is unaffected.
Affected male. Dog has or will develop XLMTM.
Beggs, A.H., Böhm, J., Snead, E., Kozlowski, M., Maurer, M., Minor, K., Childers, M.K., Taylor, S.M., Hitte, C., Mickelson, J.R., Guo, L.T., Mizisin, A.P., Buj-Bello, A., Tiret, L., Laporte, J., & Shelton, G.D. (2010). MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proceedings of the National Academy of Sciences of the United States of America, 107(33), 14697-14702. doi: 10.1073/pnas.1003677107