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

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

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA(cnm) mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA(cnm) carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA(cnm) allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.