Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide

Maurer, Marie; Mary, J.; Guillaud, Laurent; Fender, Marilyn; Pelé, Manuel; Bilzer, Thomas; Olby, Natasha J.; Penderis, Jacques; Shelton, G. Diane; Panthier, Jean‐Jacques; Thibaud, Jean-Laurent; Barthélémy, I.; Aubin-Houzelstein, Geneviève; Blot, Stéphane; Hitte, Christophe; Tiret, Laurent

doi:10.1371/journal.pone.0046408

Cited by 21 publications

(29 citation statements)

References 38 publications

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“…The initial clinical presentation of these puppies was similar to that expected with CNM, with 3‐ to 4‐month‐old puppies exhibiting weakness, muscle atrophy, absent patellar reflexes, and relatively normal serum CK activities 12, 13, 14, 15, 16, 17. There were, however, several differences between these XLMTM puppies and puppies with CNM, which prompted further evaluation.…”

Section: Discussionmentioning

confidence: 71%

“…In contrast to dogs with PTPLA mutations, clinical abnormalities in the XLMTM puppies were more severe and rapidly progressive, uniformly resulting in death or euthanasia by 15–26 weeks of age. Autosomal recessive CNM usually is a less severe, more slowly progressive disorder, with many dogs surviving into adulthood 12, 13, 14, 15, 16, 17. All of these puppies were negative for the PTPLA mutation responsible for CNM in Labrador Retrievers.…”

Section: Discussionmentioning

confidence: 95%

“…The initial clinical presentation of these puppies was similar to that expected with CNM, with 3-to 4month-old puppies exhibiting weakness, muscle atrophy, absent patellar reflexes, and relatively normal serum CK activities. [12][13][14][15][16][17] There were, however, several differences between these XLMTM puppies and puppies with CNM, which prompted further evaluation. All affected puppies were male, and pedigree analysis supported an X-linked mode of inheritance rather than the autosomal recessive inheritance typical of CNM in Labrador Retrievers.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

Snead

Taylor

Kooij

et al. 2015

Veterinary Internal Medicne

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BackgroundSeven male Labrador Retriever puppies from 3 different litters, born to clinically normal dams and sires, were evaluated for progressive weakness and muscle atrophy. Muscle biopsies identified a congenital myopathy with pathologic features consistent with myotubular myopathy. Further investigations identified a pathogenic mutation in the myotubularin gene, confirming that these puppies had X‐linked myotubular myopathy (XLMTM).ObjectiveTo review the clinical phenotype, electrodiagnostic and laboratory features of XLMTM in this cohort of Labrador Retrievers.ResultsMale puppies with XLMTM were small and thin compared with their normal littermates. Generalized weakness and muscle atrophy were present by 7 weeks of age in some puppies and evident to most owners by 14 weeks of age. Affected puppies stood with an arched spine and low head carriage, and walked with a short, choppy stride. Muscle atrophy was severe and progressive. Patellar reflexes were absent. Laryngeal and esophageal dysfunction, and weakness of the masticatory muscles occurred in puppies surviving beyond 4 months of age. Serum creatine kinase activity was normal or only mildly increased. EMG findings were nonspecific and included positive sharp waves and fibrillation potentials. Clinical signs progressed rapidly, with most affected puppies unable to walk within 3–4 weeks after clinical signs were first noticed.Conclusions and Clinical ImportanceAlthough initial clinical signs of XLMTM are similar to the phenotypically milder centronuclear myopathy in Labrador Retrievers, XLMTM is a rapidly progressive and fatal myopathy. Clinicians should be aware of these 2 distinct myopathies with similar clinical presentations in the Labrador retriever breed.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

Snead

Taylor

Kooij

et al. 2015

Veterinary Internal Medicne

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“…The proven relationship of two affected Great Dane dogs demonstrates a common origin of the BIN1 exon 11 splice mutation, and it is likely that all five affected dogs described here can be traced back to a common ancestor. As the muscle disorder is inherited as a recessive trait, and as canine pedigrees are generally highly inbred, it is likely that the mutation can be found in Great Dane dog populations from all over the world, as recently demonstrated for another autosomal recessive CNM form in Labrador retrievers [36]. It is therefore of veterinary medical interest to sequence BIN1 exon 11 in Great Dane dogs.…”

Section: Discussionmentioning

confidence: 96%

Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy

et al. 2013

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Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.

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“…C anine centronuclear myopathies (CNM) occur primarily in the Labrador retriever breed, and are inherited either as an autosomal recessive trait with full penetrance or as an X-linked condition. [1][2][3][4][5][6] As with most neuromuscular diseases in dogs, paresis is the primary clinical manifestation of CNM. Clinical signs develop within the first 1-7 months of life, and are characterized by generalized weakness and exercise intolerance, generalized muscle atrophy, and abnormal spinal reflexes.…”

mentioning

confidence: 99%

Noninvasive Assessment of Neuromuscular Disease in Dogs: Use of the 6‐minute Walk Test to Assess Submaximal Exercise Tolerance in Dogs with Centronuclear Myopathy

Cerdá-González

Talarico

Todhunter

2016

Veterinary Internal Medicne

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BackgroundNoninvasive methods of quantitating exercise tolerance in dogs with neuromuscular disease are needed both for clinical and research use. The 6‐minute walk test (6MWT) has been validated as a reliable test of exercise tolerance in dogs with pulmonary and cardiac disease, but not in dogs with neuromuscular disease.Hypothesis/ObjectivesDistance walked and number of steps taken during 6MWT will differ between Labrador retriever dogs with centronuclear myopathy (CNM) and control (ie, healthy) littermates.AnimalsEight purebred Labrador retrievers were drawn from a purpose‐bred research colony (status: 3 clear, 2 carrier, and 3 homozygous mutants for the protein tyrosine phosphatase‐like A (PTPLA) gene mutation associated with CNM).MethodsPilot, prospective, Case–controlled study. Researchers were blinded to disease status. Each dog was leash‐trained and acclimatized to the testing area (length, 12.8 m). At the start of testing, each animal was fitted with a pedometer, a timer was started, and dogs were allowed to walk at their own pace for 6 minutes. Distance walked and pedometer readings were recorded.ResultsDegree of paresis varied among affected dogs, and was reflected by significant differences in distance walked between CNM‐affected dogs and those with clear and carrier genotypes (P = .048). Pedometer readings did not vary according to genotype (P = .86).ConclusionsThe 6MWT appears to differentiate between the ambulatory capacity of normal and CNM‐affected dogs. Additional studies are needed to confirm this relationship in a larger number of dogs, and to evaluate the ability of the 6MWT to differentiate between dogs with variable severity of neuromuscular disease‐associated exercise intolerance.

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Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide

Cited by 21 publications

References 38 publications

Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

Clinical Phenotype of X‐Linked Myotubular Myopathy in Labrador Retriever Puppies

Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy

Noninvasive Assessment of Neuromuscular Disease in Dogs: Use of the 6‐minute Walk Test to Assess Submaximal Exercise Tolerance in Dogs with Centronuclear Myopathy

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